bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024‒07‒14
forty-six papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Complex Role of Regulatory T Cells (Tregs) in the Tumor Microenvironment: Their Molecular Mechanisms and Bidirectional Effects on Cancer Progression.
  2. Polarization of M2 Tumor-Associated Macrophages (TAMs) in Cancer Immunotherapy.
  3. Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer.
  4. Immune Evasion in Cancer Is Regulated by Tumor-Asociated Macrophages (TAMs): Targeting TAMs.
  5. Targeting the Depletion of M2 Macrophages: Implication in Cancer Immunotherapy.
  6. Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions.
  7. Recombinant Human IL-32θ Induces Polarization Into M1-like Macrophage in Human Monocytic Cells.
  8. Biological impact and therapeutic implication of tumor-associated macrophages in hepatocellular carcinoma.
  9. Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management.
  10. Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment.
  11. Modulating Tumor Immunity by Targeting Tumor Fibrotic Stroma and Angiogenic Vessels for Lung Cancer Treatment.
  12. Role of the Tumor Microenvironment in Mediating Resistance to Anti-HER2 Antibodies.
  13. The crosstalk between immune cells and tumor pyroptosis: advancing cancer immunotherapy strategies.
  14. Epigenetics: Mechanisms, potential roles, and therapeutic strategies in cancer progression.
  15. Expanding horizons in cancer therapy by immunoconjugates targeting tumor microenvironments.
  16. Vascular galectins in tumor angiogenesis and cancer immunity.
  17. IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.
  18. Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors.
  19. Preface: Tumor-Associated Macrophages and Tumorigenesis: Therapeutic Targeting Strategies.
  20. Myeloid‑derived suppressor cells as targets of emerging therapies and nanotherapies (Review).
  21. Construction of Hierarchically Biomimetic Iron Oxide Nanosystems for Macrophage Repolarization-Promoted Immune Checkpoint Blockade of Cancer Immunotherapy.
  22. New horizons in the mechanisms and therapeutic strategies for PD-L1 protein degradation in cancer.
  23. The Role of TAMs in the Regulation of Tumor Cell Resistance to Chemotherapy.
  24. Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma.
  25. Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis.
  26. NK Cell-Targeted Immunotherapies in Bladder Cancer: Beyond Checkpoint Inhibitors.
  27. Lactic acid: a narrative review of a promoter of the liver cancer microenvironment.
  28. Host derived macrophage migration inhibitory factor expression attenuates anti-tumoral immune cell accumulation and promotes immunosuppression in the tumor microenvironment of head and neck squamous cell carcinoma.
  29. Extracellular vesicles in oral oncology: Interplay between the tumor microenvironment and disease progression.
  30. Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.
  31. TSG-6+ cancer-associated fibroblasts modulate myeloid cell responses and impair anti-tumor response to immune checkpoint therapy in pancreatic cancer.
  32. CD36: a promising therapeutic target in hematologic tumors.
  33. The E3 ubiquitin ligase FBXO38 maintains the antitumor function of natural killer cells by sustaining IL-15R signaling.
  34. Role of Protein Phosphatases in Tumor Angiogenesis: Assessing PP1, PP2A, PP2B and PTPs Activity.
  35. Modulation of purinergic signaling in endothelial cells by tumor microenvironment.
  36. Emerging roles of CAR-NK cell therapies in tumor immunotherapy: current status and future directions.
  37. Myeloid-derived Suppressor Cells and Multiple Sclerosis.
  38. Reactive oxygen species/glutathione dual sensitive nanoparticles with encapsulation of miR155 and curcumin for synergized cancer immunotherapy.
  39. The effect of exercise and disease status on mobilization of anti-tumorigenic and pro-tumorigenic immune cells in women with breast cancer.
  40. Medulloblastoma Spatial Transcriptomics Reveals Tumor Microenvironment Heterogeneity with High-Density Progenitor Cell Regions Correlating with High-Risk Disease.
  41. Mesenchymal Stem Cell-Secreted Exosomes and Soluble Signals Regulate Breast Cancer Metastatic Dormancy: Current Progress and Future Outlook.
  42. Gender difference of bladder cancer: insights from hormone, anatomy and tumor microenvironment.
  43. Tumor Dormancy and Reactivation: The Role of Heat Shock Proteins.
  44. Pantoprazole and riluzole target H+/K+-ATPases and pH-sensitive K+ channels in pancreatic cancer cells.
  45. Enhanced RHO-ROCK signaling is associated with CRELD2 production and fibroblast recruitment in cutaneous squamous cell carcinoma.
  46. Hypothesis: the generation of T cells directed against neoepitopes employing immune-mediating agents other than neoepitope vaccines.
  1. Int J Mol Sci. 2024 Jul 04. pii: 7346. [Epub ahead of print]25(13):
    Complex Role of Regulatory T Cells (Tregs) in the Tumor Microenvironment: Their Molecular Mechanisms and Bidirectional Effects on Cancer Progression.
    Yu Wang, Jiazhou Li, Shingo Nakahata, Hidekatsu Iha.
      Regulatory T cells (Tregs) possess unique immunosuppressive activity among CD4-positive T cells. Tregs are ubiquitously present in mammals and function to calm excessive immune responses, thereby suppressing allergies or autoimmune diseases. On the other hand, due to their immunosuppressive function, Tregs are thought to promote cancer progression. The tumor microenvironment (TME) is a multicellular system composed of many cell types, including tumor cells, infiltrating immune cells, and cancer-associated fibroblasts (CAFs). Within this environment, Tregs are recruited by chemokines and metabolic factors and impede effective anti-tumor responses. However, in some cases, their presence can also improve patient's survival rates. Their functional consequences may vary across tumor types, locations, and stages. An in-depth understanding of the precise roles and mechanisms of actions of Treg is crucial for developing effective treatments, emphasizing the need for further investigation and validation. This review aims to provide a comprehensive overview of the complex and multifaceted roles of Tregs within the TME, elucidating cellular communications, signaling pathways, and their impacts on tumor progression and highlighting their potential anti-tumor mechanisms through interactions with functional molecules.
    Keywords:  cancer; chemokine; regulatory T cells (Tregs); tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/ijms25137346
  2. Crit Rev Oncog. 2024 ;29(4): 75-95
    Polarization of M2 Tumor-Associated Macrophages (TAMs) in Cancer Immunotherapy.
    Indy Bui, Benjamin Bonavida.
      We have witnessed in the last decade new milestones in the treatment of various resistant cancers with new immunotherapeutic modalities. These advances have resulted in significant objective durable clinical responses in a subset of cancer patients. These findings strongly suggested that immunotherapy should be considered for the treatment of all subsets of cancer patients. Accordingly, the mechanisms underlying resistance to immunotherapy must be explored and develop new means to target these resistant factors. One of the pivotal resistance mechanisms in the tumor microenvironment (TME) is the high infiltration of tumor-associated macrophages (TAMs) that are highly immunosuppressive and responsible, in large part, of cancer immune evasion. Thus, various approaches have been investigated to target the TAMs to restore the anti-tumor immune response. One approach is to polarize the M2 TAMS to the M1 phenotype that participates in the activation of the anti-tumor response. In this review, we discuss the various and differential properties of the M1 and M2 phenotypes, the molecular signaling pathways that participate in the polarization, and various approaches used to target the polarization of the M2 TAMs into the M1 anti-tumor phenotype. These approaches include inhibitors of histone deacetylases, PI3K inhibitors, STAT3 inhibitors, TLR agonists, and metabolic reprogramming. Clearly, due to the distinct features of various cancers and their heterogeneities, a single approach outlined above might only be effective against some cancers and not others. In addition, targeting by itself may not be efficacious unless used in combination with other therapeutic modalities.
    DOI:  https://doi.org/10.1615/CritRevOncog.2024053830
  3. Proc Natl Acad Sci U S A. 2024 Jul 16. 121(29): e2403917121
    Intratumoral NKT cell accumulation promotes antitumor immunity in pancreatic cancer.
    Jiayun Li, Philip Moresco, Douglas T Fearon.
      Pancreatic ductal adenocarcinoma (PDA) is a potentially lethal disease lacking effective treatments. Its immunosuppressive tumor microenvironment (TME) allows it to evade host immunosurveillance and limits response to immunotherapy. Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells is required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an antitumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells, and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the therapeutic potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.
    Keywords:  CD40–CD40L interaction; NKT cells; folinic acid; tumor microenvironment; type I IFN
    DOI:  https://doi.org/10.1073/pnas.2403917121
  4. Crit Rev Oncog. 2024 ;29(4): 1-17
    Immune Evasion in Cancer Is Regulated by Tumor-Asociated Macrophages (TAMs): Targeting TAMs.
    Megan Jung, Benjamin Bonavida.
      Recent advancements in cancer treatment have explored a variety of approaches to address the needs of patients. Recently, immunotherapy has evolved as an efficacious treatment for various cancers resistant to conventional therapies. Hence, significant milestones in immunotherapy were achieved clinically in a large subset of cancer patients. Unfortunately, some cancer types do not respond to treatment, and among the responsive cancers, some patients remain unresponsive to treatment. Consequently, there is a critical need to examine the mechanisms of immune resistance and devise strategies to target immune suppressor cells or factors, thereby allowing for tumor sensitivity to immune cytotoxic cells. M2 macrophages, also known as tumor-associated macrophages (TAMs), are of interest due to their role in suppressing the immune system and influencing antitumor immune responses through modulating T cell activity and immune checkpoint expression. TAMs are associated with signaling pathways that modulate the tumor microenvironment (TME), contributing to immune evasion. One approach targets TAMs, focusing on preventing the polarization of M1 macrophages into the protumoral M2 phenotype. Other strategies focus on direct or indirect targeting of M2 macrophages through understanding the interaction of TAMs with immune factors or signaling pathways. Clinically, biomarkers associated with TAMs' immune resistance in cancer patients have been identified, opening avenues for intervention using pharmacological agents or immunotherapeutic approaches. Ultimately, these multifaceted approaches are promising in overcoming immune resistance and improving cancer treatment outcomes.
    DOI:  https://doi.org/10.1615/CritRevOncog.2024053096
  5. Crit Rev Oncog. 2024 ;29(4): 55-73
    Targeting the Depletion of M2 Macrophages: Implication in Cancer Immunotherapy.
    Talia Festekdjian, Benjamin Bonavida.
      We have witnessed the emergence of immunotherapy against various cancers that resulted in significant clinical responses and particularly in cancers that were resistant to chemotherapy. These milestones have ignited the development of novel strategies to boost the anti-tumor immune response for immune-suppressed tumors in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are the most abundant cells in the TME, and their frequency correlates with poor prognosis. Hence, several approaches have been developed to target TAMs in effort to restore the anti-tumor immune response and inhibit tumor growth and metastasis. One approach discussed herein is targeting TAMs via their depletion. Several methods have been reported for TAMs depletion including micro-RNAs, transcription factors (e.g., PPARγ, KLF4, STAT3, STAT6, NF-κB), chemokines and chemokine receptors, antibodies-mediated blocking the CSF-1/CSF-1R pathway, nanotechnology, and various combination treatments. In addition, various clinical trials are currently examining the targeting of TAMs. Many of these methods also have side effects that need to be monitored and reduced. Future perspectives and directions are discussed.
    DOI:  https://doi.org/10.1615/CritRevOncog.2024053580
  6. Cancers (Basel). 2024 Jul 02. pii: 2438. [Epub ahead of print]16(13):
    Decoding the Intricate Landscape of Pancreatic Cancer: Insights into Tumor Biology, Microenvironment, and Therapeutic Interventions.
    Antonella Argentiero, Alessandro Andriano, Ingrid Catalina Caradonna, Giulia de Martino, Vanessa Desantis.
      Pancreatic ductal adenocarcinoma (PDAC) presents significant oncological challenges due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) plays a critical role in progression and treatment resistance. Non-neoplastic cells, such as cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), contribute to tumor growth, angiogenesis, and immune evasion. Although immune cells infiltrate TME, tumor cells evade immune responses by secreting chemokines and expressing immune checkpoint inhibitors (ICIs). Vascular components, like endothelial cells and pericytes, stimulate angiogenesis to support tumor growth, while adipocytes secrete factors that promote cell growth, invasion, and treatment resistance. Additionally, perineural invasion, a characteristic feature of PDAC, contributes to local recurrence and poor prognosis. Moreover, key signaling pathways including Kirsten rat sarcoma viral oncogene (KRAS), transforming growth factor beta (TGF-β), Notch, hypoxia-inducible factor (HIF), and Wnt/β-catenin drive tumor progression and resistance. Targeting the TME is crucial for developing effective therapies, including strategies like inhibiting CAFs, modulating immune response, disrupting angiogenesis, and blocking neural cell interactions. A recent multi-omic approach has identified signature genes associated with anoikis resistance, which could serve as prognostic biomarkers and targets for personalized therapy.
    Keywords:  Notch signaling; PD-L1; TGF-beta signaling; cancer-associated fibroblasts; macrophages; pancreatic cancer; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cancers16132438
  7. Immune Netw. 2024 Jun;24(3): e27
    Recombinant Human IL-32θ Induces Polarization Into M1-like Macrophage in Human Monocytic Cells.
    Hyo-Min Park, Jae-Young Park, Na-Yeon Kim, Hyemoon Kim, Hong-Gyum Kim, Dong-Ju Son, Jin Tae Hong, Do-Young Yoon.
      The tumor microenvironment (TME) is formed by several immune cells. Notably, tumor-associated macrophages (TAMs) are existed in the TME that induce angiogenesis, metastasis, and proliferation of cancer cells. Recently, a point-mutated variant of IL-32θ was discovered in breast cancer tissues, which suppressed migration and proliferation through intracellular pathways. Although the relationship between cancer and IL-32 has been previously studied, the effects of IL-32θ on TAMs remain elusive. Recombinant human IL-32θ (rhIL-32θ) was generated using an Escherichia coli expression system. To induce M0 macrophage polarization, THP-1 cells were stimulated with PMA. After PMA treatment, the cells were cultured with IL-4 and IL-13, or rhIL-32θ. The mRNA level of M1 macrophage markers (IL-1β, TNFα, inducible nitric oxide synthase) were increased by rhIL-32θ in M0 macrophages. On the other hand, the M2 macrophage markers (CCL17, CCL22, TGFβ, CD206) were decreased by rhIL-32θ in M2 macrophages. rhIL-32θ induced nuclear translocation of the NF-κB via regulation of the MAPK (p38) pathway. In conclusion, point-mutated rhIL-32θ induced the polarization to M1-like macrophages through the MAPK (p38) and NF-κB (p65/p50) pathways.
    Keywords:  IL-32θ; Immunotherapy; Inflammation; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.4110/in.2024.24.e27
  8. Cell Death Dis. 2024 Jul 12. 15(7): 498
    Biological impact and therapeutic implication of tumor-associated macrophages in hepatocellular carcinoma.
    Deming Li, Ting Zhang, Ye Guo, Cong Bi, Ming Liu, Gang Wang.
      The tumor microenvironment is a complex space comprised of normal, cancer and immune cells. The macrophages are considered as the most abundant immune cells in tumor microenvironment and their function in tumorigenesis is interesting. Macrophages can be present as M1 and M2 polarization that show anti-cancer and oncogenic activities, respectively. Tumor-associated macrophages (TAMs) mainly have M2 polarization and they increase tumorigenesis due to secretion of factors, cytokines and affecting molecular pathways. Hepatocellular carcinoma (HCC) is among predominant tumors of liver that in spite of understanding its pathogenesis, the role of tumor microenvironment in its progression still requires more attention. The presence of TAMs in HCC causes an increase in growth and invasion of HCC cells and one of the reasons is induction of glycolysis that such metabolic reprogramming makes HCC distinct from normal cells and promotes its malignancy. Since M2 polarization of TAMs stimulates tumorigenesis in HCC, molecular networks regulating M2 to M1 conversion have been highlighted and moreover, drugs and compounds with the ability of targeting TAMs and suppressing their M2 phenotypes or at least their tumorigenesis activity have been utilized. TAMs increase aggressive behavior and biological functions of HCC cells that can result in development of therapy resistance. Macrophages can provide cell-cell communication in HCC by secreting exosomes having various types of biomolecules that transfer among cells and change their activity. Finally, non-coding RNA transcripts can mainly affect polarization of TAMs in HCC.
    DOI:  https://doi.org/10.1038/s41419-024-06888-z
  9. Immune Netw. 2024 Jun;24(3): e26
    Exploring the Potential of Glycolytic Modulation in Myeloid-Derived Suppressor Cells for Immunotherapy and Disease Management.
    Jisu Kim, Jee Yeon Choi, Hyeyoung Min, Kwang Woo Hwang.
      Recent advancements in various technologies have shed light on the critical role of metabolism in immune cells, paving the way for innovative disease treatment strategies through immunometabolism modulation. This review emphasizes the glucose metabolism of myeloid-derived suppressor cells (MDSCs), an emerging pivotal immunosuppressive factor especially within the tumor microenvironment. MDSCs, an immature and heterogeneous myeloid cell population, act as a double-edged sword by exacerbating tumors or mitigating inflammatory diseases through their immune-suppressive functions. Numerous recent studies have centered on glycolysis of MDSC, investigating the regulation of altered glycolytic pathways to manage diseases. However, the specific changes in MDSC glycolysis and their exact functions continue to be areas of ongoing discussion yet. In this paper, we review a range of current findings, including the latest research on the alteration of glycolysis in MDSCs, the consequential functional alterations in these cells, and the outcomes of attempts to modulate MDSC functions by regulating glycolysis. Ultimately, we will provide insights into whether these research efforts could be translated into clinical applications.
    Keywords:  Glycolysis; Immunomodulation; Metabolic reprogramming; Myeloid-derived suppressor cell
    DOI:  https://doi.org/10.4110/in.2024.24.e26
  10. Cancer Commun (Lond). 2024 Jul 12.
    Cellular senescence and metabolic reprogramming: Unraveling the intricate crosstalk in the immunosuppressive tumor microenvironment.
    Fusheng Zhang, Junchen Guo, Shengmiao Yu, Youwei Zheng, Meiqi Duan, Liang Zhao, Yihan Wang, Zhi Yang, Xiaofeng Jiang.
      The intrinsic oncogenic mechanisms and properties of the tumor microenvironment (TME) have been extensively investigated. Primary features of the TME include metabolic reprogramming, hypoxia, chronic inflammation, and tumor immunosuppression. Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME. Specifically, hypoxic adaptation, metabolic dysregulation, and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation, thereby promoting the progression of tumor events. This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME, with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells. The available findings suggest that components of the TME collectively contribute to the progression of tumor events. The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.
    Keywords:  cellular senescence; chronic inflammation; hypoxia; immunosuppressive tumor microenvironment; metabolic reprogramming; tumor‐targeted therapy
    DOI:  https://doi.org/10.1002/cac2.12591
  11. Cancers (Basel). 2024 Jul 08. pii: 2483. [Epub ahead of print]16(13):
    Modulating Tumor Immunity by Targeting Tumor Fibrotic Stroma and Angiogenic Vessels for Lung Cancer Treatment.
    Yi Yuan, Falguni Mishra, Bin Li, Guangda Peng, Payton Chan, Jenny Yang, Zhiren Liu.
      Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin αvβ3. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD4+ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD8+ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment.
    Keywords:  cancer-associated fibroblasts; checkpoint blockade; immunotherapy; integrin αvβ3; tumor immunity; tumor vessels
    DOI:  https://doi.org/10.3390/cancers16132483
  12. Crit Rev Oncog. 2024 ;29(4): 43-54
    Role of the Tumor Microenvironment in Mediating Resistance to Anti-HER2 Antibodies.
    Manoj Kumar Gupta, Gayatri Gouda, Ramakrishna Vadde.
      Breast cancer (BC) is the most common cancer and the second leading cause of cancer-related deaths in women globally. Despite advancements in treatment strategies, many patients still develop challenging-to-treat metastatic disease. The development and progression of tumors are influenced by genetic/epigenetic changes within tumor cells and alterations in the tumor microenvironment (TME) through a dynamic communication. The TME comprises various elements, including immune, tumor, and stromal cells. Tumor cells at the core of the TME orchestrate complex signals that lead to tumor growth, survival, and resistance to treatment. Human epidermal growth factor receptor 2 (HER2) is overexpressed in a significant proportion of invasive breast cancers, influencing prognosis and prediction. Novel therapeutic approaches target HER2-positive breast cancers by leveraging HER2-targeted therapeuirtcs such as antibody-drug conjugates, monoclonal antibodies, and tyrosine kinase inhibitors. The TME in HER2-positive breast cancers also involves cancer-associated fibroblasts and cancer-associated adipocytes, which play critical roles in tumor progression and therapy resistance. The immune microenvironment also plays a significant role, with studies indicating its impact on outcomes in HER2-positive breast cancer. Trastuzumab, one of the first monoclonal antibodies targeting HER2, has shown promise in enhancing survival rates in HER2-overexpressing breast cancer. Integration of trastuzumab with chemotherapy has demonstrated significant enhancements in disease-free survival as well as overall survival rates during early breast cancer treatment. Trastuzumab functions by inhibiting HER2 signaling pathways, leading to cell cycle arrest and induction of apoptosis. Overall, understanding the complex interplay between HER2, the tumor microenvironment, and therapeutic interventions is essential for improving outcomes in HER2-positive BC.
    DOI:  https://doi.org/10.1615/CritRevOncog.2024053419
  13. J Exp Clin Cancer Res. 2024 Jul 10. 43(1): 190
    The crosstalk between immune cells and tumor pyroptosis: advancing cancer immunotherapy strategies.
    Mengyuan Hu, Fengying Deng, Xinlei Song, Hongkun Zhao, Fei Yan.
      Pyroptosis is a cell death process characterized by cell swelling until membrane rupture and release of intracellular contents. As an effective tumor treatment strategy, inducing tumor cell pyroptosis has received widespread attention. In this process, the immune components within the tumor microenvironment play a key regulatory role. By regulating and altering the functions of immune cells such as cytotoxic T lymphocytes, natural killer cells, tumor-associated macrophages, and neutrophils, tumor cell pyroptosis can be induced. This article provides a comprehensive review of the molecular mechanisms of cell pyroptosis, the impact of the tumor immune microenvironment on tumor cell pyroptosis, and its mechanisms. It aims to gain an in-depth understanding of the communication between the tumor immune microenvironment and tumor cells, and to provide theoretical support for the development of new tumor immunotherapies.
    Keywords:  Immune cells; Immunotherapies; Pyroptosis; Tumor; Tumor immune microenvironment
    DOI:  https://doi.org/10.1186/s13046-024-03115-7
  14. Genes Dis. 2024 Sep;11(5): 101020
    Epigenetics: Mechanisms, potential roles, and therapeutic strategies in cancer progression.
    Dong Wang, Yan Zhang, Qingbo Li, Yu Li, Wen Li, Ao Zhang, Jingxuan Xu, Jingyan Meng, Lin Tang, Shuhua Lyu.
      Mutations or abnormal expression of oncogenes and tumor suppressor genes are known to cause cancer. Recent studies have shown that epigenetic modifications are key drivers of cancer development and progression. Nevertheless, the mechanistic role of epigenetic dysregulation in the tumor microenvironment is not fully understood. Here, we reviewed the role of epigenetic modifications of cancer cells and non-cancer cells in the tumor microenvironment and recent research advances in cancer epigenetic drugs. In addition, we discussed the great potential of epigenetic combination therapies in the clinical treatment of cancer. However, there are still some challenges in the field of cancer epigenetics, such as epigenetic tumor heterogeneity, epigenetic drug heterogeneity, and crosstalk between epigenetics, proteomics, metabolomics, and other omics, which may be the focus and difficulty of cancer treatment in the future. In conclusion, epigenetic modifications in the tumor microenvironment are essential for future epigenetic drug development and the comprehensive treatment of cancer. Epigenetic combination therapy may be a novel strategy for the future clinical treatment of cancer.
    Keywords:  Cancer; Epigenetics; Gene expression; Heterogeneity; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.gendis.2023.04.040
  15. Crit Rev Oncol Hematol. 2024 Jul 06. pii: S1040-8428(24)00180-X. [Epub ahead of print] 104437
    Expanding horizons in cancer therapy by immunoconjugates targeting tumor microenvironments.
    Amir Saamaan Fattahi, Mahboobeh Jafari, Ghazal Farahavar, Samira Sadat Abolmaali, Ali Mohammad Tamaddon.
      Immunoconjugates are promising molecules combining antibodies with different agents, such as toxins, drugs, radionuclides, or cytokines that primarily aim to target tumor cells. However, tumor microenvironment (TME), which comprises a complex network of various cells and molecular cues guiding tumor growth and progression, remains a major challenge for effective cancer therapy. Our review underscores the pivotal role of TME in cancer therapy with immunoconjugates, examining the intricate interactions with TME and recent advancements in TME-targeted immunoconjugates. We explore strategies for targeting TME components, utilizing diverse antibodies such as neutralizing, immunomodulatory, immune checkpoint inhibitors, immunostimulatory, and bispecific antibodies. Additionally, we discuss different immunoconjugates, elucidating their mechanisms of action, advantages, limitations, and applications in cancer immunotherapy. Furthermore, we highlight emerging technologies enhancing the safety and efficacy of immunoconjugates, such as antibody engineering, combination therapies, and nanotechnology. Finally, we summarize current advancements, perspectives, and future developments of TME-targeted immunoconjugates.
    Keywords:  TME; antibody; cancer immunotherapy; immunoconjugates; targeting
    DOI:  https://doi.org/10.1016/j.critrevonc.2024.104437
  16. Semin Immunopathol. 2024 Jul 11. 46(1-2): 3
    Vascular galectins in tumor angiogenesis and cancer immunity.
    Victor L J L Thijssen.
      Sustained tumor angiogenesis, i.e., the induction and maintenance of blood vessel growth by tumor cells, is one of the hallmarks of cancer. The vascularization of malignant tissues not only facilitates tumor growth and metastasis, but also contributes to immune evasion. Important players in all these processes are the endothelial cells which line the luminal side of blood vessel. In the tumor vasculature, these cells are actively involved in angiogenesis as well in the hampered recruitment of immune cells. This is the result of the abnormal tumor microenvironment which triggers both angiostimulatory and immune inhibitory gene expression profiles in endothelial cells. In recent years, it has become evident that galectins constitute a protein family that is expressed in the tumor endothelium. Moreover, several members of this glycan-binding protein family have been found to facilitate tumor angiogenesis and stimulate immune suppression. All this has identified galectins as potential therapeutic targets to simultaneously hamper tumor angiogenesis and alleviate immune suppression. The current review provides a brief introduction in the human galectin protein family. The current knowledge regarding the expression and regulation of galectins in endothelial cells is summarized. Furthermore, an overview of the role that endothelial galectins play in tumor angiogenesis and tumor immunomodulation is provided. Finally, some outstanding questions are discussed that should be addressed by future research efforts. This will help to fully understand the contribution of endothelial galectins to tumor progression and to exploit endothelial galectins for cancer therapy.
    Keywords:  Endothelium; Glycosylation; Immune cells; Immune check point; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00281-024-01014-9
  17. Neuro Oncol. 2024 Jul 10. pii: noae126. [Epub ahead of print]
    IL-13Rα2/TGF-β bispecific CAR-T cells counter TGF-β-mediated immune suppression and potentiate anti-tumor responses in glioblastoma.
    Andrew J Hou, Ryan M Shih, Benjamin R Uy, Amanda Shafer, Ze Nan L Chang, Begonya Comin-Anduix, Miriam Guemes, Zoran Galic, Su Phyu, Hideho Okada, Katie B Grausam, Joshua J Breunig, Christine E Brown, David A Nathanson, Robert M Prins, Yvonne Y Chen.
      BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies targeting glioblastoma (GBM)-associated antigens such as interleukin-13 receptor subunit alpha-2 (IL-13Rα2) have achieved limited clinical efficacy to date, in part due to an immunosuppressive tumor microenvironment (TME) characterized by inhibitory molecules such as transforming growth factor-beta (TGF-β). The aim of this study was to engineer more potent GBM-targeting CAR-T cells by countering TGF-β-mediated immune suppression in the TME.METHODS: We engineered a single-chain, bispecific CAR targeting IL-13Rα2 and TGF-β, which programs tumor-specific T cells to convert TGF-β from an immunosuppressant to an immunostimulant. Bispecific IL-13Rα2/TGF-β CAR-T cells were evaluated for efficacy and safety against both patient-derived GBM xenografts and syngeneic models of murine glioma.
    RESULTS: Treatment with IL-13Rα2/TGF-β CAR-T cells leads to greater T-cell infiltration and reduced suppressive myeloid cell presence in the tumor-bearing brain compared to treatment with conventional IL-13Rα2 CAR-T cells, resulting in improved survival in both patient-derived GBM xenografts and syngeneic models of murine glioma.
    CONCLUSION: Our findings demonstrate that by reprogramming tumor-specific T-cell responses to TGF-β, bispecific IL-13Rα2/TGF-β CAR-T cells resist and remodel the immunosuppressive TME to drive potent anti-tumor responses in GBM.
    Keywords:  CAR-T cell therapy; Immunotherapy; TGF-β; glioblastoma; tumor microenvironment
    DOI:  https://doi.org/10.1093/neuonc/noae126
  18. Cancer Res. 2024 Jul 11.
    Ionizable STING-Activating Nanoadjuvants Enhance Tumor Immunogenicity and Potentiate Immunotherapy Efficacy in Solid Tumors.
    Shiyun Xian, Xiaona Chen, Sihang Ren, Xiaolong Chen, Hangxiang Wang.
      Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the STING pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment (TME). The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic TME, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3511
  19. Crit Rev Oncog. 2024 ;29(4): vii-viii
    Preface: Tumor-Associated Macrophages and Tumorigenesis: Therapeutic Targeting Strategies.
    Benjamin Bonavida.
      
  20. Med Int (Lond). 2024 Sep-Oct;4(5):4(5): 46
    Myeloid‑derived suppressor cells as targets of emerging therapies and nanotherapies (Review).
    Dileep Kumar, Victor Carlos Da Silva, Natalia Lemos Chaves.
      Breast cancer (BC) is the leading cause of cancer-related mortality among women worldwide. Immunotherapies are a promising approach in cancer treatment, particularly for aggressive forms of BC with high mortality rates. However, the current eligibility for immunotherapy remains limited to a limited fraction of patients with BC. Myeloid-derived suppressor cells (MDSCs), originating from myeloid cells, are known for their dual role in immunosuppression and tumor promotion, significantly affecting patient outcomes by fostering the formation of premetastatic niches. Consequently, targeting MDSCs has emerged as a promising avenue for further exploration in therapeutic interventions. Leveraging nanotechnology-based drug delivery systems, which excel in accumulating drugs within tumors via passive or active targeting mechanisms, are a promising strategy for the use of MDSCs in the treatment of BC. The present review discusses the immunosuppressive functions of MDSCs, their role in BC, and the diverse strategies for targeting them in cancer therapy. Additionally, the present review discusses future advancements in BC treatments focusing on MDSCs. Furthermore, it elucidates the mechanisms underlying MDSC activation, recruitment and differentiation in BC progression, highlighting the clinical characteristics that render MDSCs suitable candidates for the therapy and targeted nanotherapy of BC.
    Keywords:  breast cancer; immunosuppression; immunotherapy; myeloid-derived suppressor cells; nanotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3892/mi.2024.170
  21. ACS Appl Mater Interfaces. 2024 Jul 09.
    Construction of Hierarchically Biomimetic Iron Oxide Nanosystems for Macrophage Repolarization-Promoted Immune Checkpoint Blockade of Cancer Immunotherapy.
    Yaqing Kang, Jiao Yan, Xiaoqing Han, Xingbo Wang, Yanjing Wang, Panpan Song, Xiaochen Su, Abdur Rauf, Xuefei Jin, Fang Pu, Haiyuan Zhang.
      Cancer immunotherapy is developing as the mainstream strategy for treatment of cancer. However, the interaction between the programmed cell death protein-1 (PD-1) and the programmed death ligand 1 (PD-L1) restricts T cell proliferation, resulting in the immune escape of tumor cells. Recently, immune checkpoint inhibitor therapy has achieved clinical success in tumor treatment through blocking the PD-1/PD-L1 checkpoint pathway. However, the presence of M2 tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) will inhibit antitumor immune responses and facilitate tumor growth, which can weaken the effectiveness of immune checkpoint inhibitor therapy. The repolarization of M2 TAMs into M1 TAMs can induce the immune response to secrete proinflammatory factors and active T cells to attack tumor cells. Herein, hollow iron oxide (Fe3O4) nanoparticles (NPs) were prepared for reprogramming M2 TAMs into M1 TAMs. BMS-202, a small-molecule PD-1/PD-L1 inhibitor that has a lower price, higher stability, lower immunogenicity, and higher tumor penetration ability compared with antibodies, was loaded together with pH-sensitive NaHCO3 inside hollow Fe3O4 NPs, followed by wrapping with macrophage membranes. The formed biomimetic FBN@M could produce gaseous carbon dioxide (CO2) from NaHCO3 in response to the acidic TME, breaking up the macrophage membranes to release BMS-202. A series of in vitro and in vivo assessments revealed that FBN@M could reprogram M2 TAMs into M1 TAMs and block the PD-1/PD-L1 pathway, which eventually induced T cell activation and the secretion of TNF-α and IFN-γ to kill the tumor cells. FBN@M has shown a significant immunotherapeutic efficacy for tumor treatment.
    Keywords:  cancer immunotherapy; hollow iron oxide; macrophage membranes; macrophage repolarization; small molecular checkpoint inhibitors
    DOI:  https://doi.org/10.1021/acsami.4c06415
  22. Biochim Biophys Acta Rev Cancer. 2024 Jul 09. pii: S0304-419X(24)00083-0. [Epub ahead of print] 189152
    New horizons in the mechanisms and therapeutic strategies for PD-L1 protein degradation in cancer.
    Zhi Li, Xi Yu, Zeting Yuan, Lei Li, Peihao Yin.
      Programmed death-ligand 1 (PD-L1) has become a crucial focus in cancer immunotherapy considering it is found in many different cells. Cancer cells enhance the suppressive impact of programmed death receptor 1 (PD-1) through elevating PD-L1 expression, which allows them to escape immune detection. Although there have been significant improvements, the effectiveness of anti-PD-1/PD-L1 treatment is still limited to a specific group of patients. An important advancement in cancer immunotherapy involves improving the PD-L1 protein degradation. This review thoroughly examined the processes by which PD-L1 breaks down, including the intracellular pathways of ubiquitination-proteasome and autophagy-lysosome. In addition, the analysis revealed changes that affect PD-L1 stability, such as phosphorylation and glycosylation. The significant consequences of these procedures on cancer immunotherapy and their potential role in innovative therapeutic approaches are emphasised. Our future efforts will focus on understanding new ways in which PD-L1 degradation is controlled and developing innovative treatments, such as proteolysis-targeting chimeras designed specifically to degrade PD-L1. It is crucial to have a thorough comprehension of these pathways in order to improve cancer immunotherapy strategies and hopefully improve therapeutic effectiveness.
    Keywords:  Degradation; Immunotherapy; Programmed death receptor 1; Programmed death-ligand 1; Proteolysis-targeting chimeras; Ubiquitination
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189152
  23. Crit Rev Oncog. 2024 ;29(4): 97-125
    The Role of TAMs in the Regulation of Tumor Cell Resistance to Chemotherapy.
    Ryan McWhorter, Benjamin Bonavida.
      Tumor-associated macrophages (TAMs) are the predominant cell infiltrate in the immunosuppressive tumor microenvironment (TME). TAMs are central to fostering pro-inflammatory conditions, tumor growth, metastasis, and inhibiting therapy responses. Many cancer patients are innately refractory to chemotherapy and or develop resistance following initial treatments. There is a clinical correlation between the level of TAMs in the TME and chemoresistance. Hence, the pivotal role of TAMs in contributing to chemoresistance has garnered significant attention toward targeting TAMs to reverse this resistance. A prerequisite for such an approach requires a thorough understanding of the various underlying mechanisms by which TAMs inhibit response to chemotherapeutic drugs. Such mechanisms include enhancing drug efflux, regulating drug metabolism and detoxification, supporting cancer stem cell (CSCs) resistance, promoting epithelial-mesenchymal transition (EMT), inhibiting drug penetration and its metabolism, stimulating angiogenesis, impacting inhibitory STAT3/NF-κB survival pathways, and releasing specific inhibitory cytokines including TGF-β and IL-10. Accordingly, several strategies have been developed to overcome TAM-modulated chemoresistance. These include novel therapies that aim to deplete TAMs, repolarize them toward the anti-tumor M1-like phenotype, or block recruitment of monocytes into the TME. Current results from TAM-targeted treatments have been unimpressive; however, the use of TAM-targeted therapies in combination appears promising These include targeting TAMs with radiotherapy, chemotherapy, chemokine receptor inhibitors, immunotherapy, and loaded nanoparticles. The clinical limitations of these strategies are discussed.
    DOI:  https://doi.org/10.1615/CritRevOncog.2024053667
  24. J Immunother Cancer. 2024 Jul 08. pii: e008811. [Epub ahead of print]12(7):
    Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma.
    Yang Chen, Yu Zhou, Ran Ren, Yu Chen, Juan Lei, Yongsheng Li.
      BACKGROUND: While anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in patients with lung adenocarcinoma may hinder the efficacy of anti-PD-1 monotherapy.METHODS: Here, we delved into the patterns of lipid metabolism in patients with The Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and their correlation with the immune microenvironment's cellular infiltration characteristics of the tumor. Furthermore, the lipid metabolism score (LMS) system was constructed, and based on the LMS system, we further performed screening for potential agents targeting lipid metabolism. The mechanism of MK1775 was further validated using RNA sequencing, co-culture technology, and in vivo experiments.
    RESULTS: We developed an LSM system and identified a potential sensitizing agent, MK1775, which targets lipid metabolism and enhances the effects of anti-PD-1 treatment. Our results demonstrate that MK1775 inhibits tumor progression by influencing lipid crosstalk between tumor cells and tumor-associated macrophages and CD8+T cells, thereby increasing the effectiveness of anti-PD-1 treatment. Further, we found that MK1775 inhibited the phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which on one hand downregulated FASN-mediated synthesis of fatty acids (FAs) to inhibit fatty acid oxidation of tumor-associated macrophages, and on the other hand, promoted IRF-mediated secretion of CXCL10 and CXCL11 to facilitate the infiltration of CD8+ T cells.
    CONCLUSIONS: These findings emphasize the important role of lipid metabolism in shaping the complex tumor microenvironment. By manipulating the intricate intricacies of lipid metabolism within the tumor microenvironment, we can uncover and develop promising strategies to sensitize immunotherapy, potentially revolutionizing cancer treatment approaches.
    Keywords:  Immune Checkpoint Inhibitor; Lung Cancer; Macrophage; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2024-008811
  25. bioRxiv. 2024 Jun 25. pii: 2024.06.20.599939. [Epub ahead of print]
    Targeting MDSC-HTR2B to Improve Immune Checkpoint Inhibitors in Breast to Brain Metastasis.
    Mukund Iyer, Diganta Das, Aaron G Baugh, Priya Shah, Brooke Nakamura, Saman Sedighi, Max Reed, Julie Jang, Frances Chow, Evanthia Roussos Torres, Josh Neman.
      Myeloid Derived Suppressor Cells (MDSCs) support breast cancer growth via immune suppression and non-immunological mechanisms. Although 15% of patients with breast cancer will develop brain metastasis, there is scant understanding of MDSCs' contribution within the breast-to-brain metastatic microenvironment. Utilizing co-culture models mimicking a tumor-neuron-immune microenvironment and patient tissue arrays, we identified serotonergic receptor, HTR2B, on MDSCs to upregulate pNF-κB and suppress T cell proliferation, resulting in enhanced tumor growth. In vivo murine models of metastatic and intracranial breast tumors treated with FDA-approved, anti-psychotic HTR2B antagonist, clozapine, combined with immunotherapy anti-PD-1 demonstrated a significant increase in survival and increased T cell infiltration. Collectively, these findings reveal a previously unknown role of MDSC-HTR2B in breast-to-brain metastasis, suggesting a novel and immediate therapeutic approach using neurological drugs to treat patients with metastatic breast cancer.
    DOI:  https://doi.org/10.1101/2024.06.20.599939
  26. Bladder Cancer. 2023 ;9(2): 125-139
    NK Cell-Targeted Immunotherapies in Bladder Cancer: Beyond Checkpoint Inhibitors.
    Yuanshuo A Wang, Daniel Ranti, Christine Bieber, Matthew Galsky, Nina Bhardwaj, John P Sfakianos, Amir Horowitz.
      BACKGROUND: For decades, immunotherapies have been integral for the treatment and management of bladder cancer, with immune checkpoint inhibitors (ICIs) transforming patient care in recent years. However, response rates are poor to T cell-targeted ICIs such as programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies, framing a critical need for complementary immunotherapies. Promising strategies involve harnessing the activation potential of natural killer (NK) cells. They quickly exert their antitumor activity via signaling through germline-encoded activating receptors and are rapidly sensitized to new tissue microenvironments via their regulation by polymorphic HLA class I, KIR and NKG2A receptors.OBJECTIVE: In this review, we examined the roles of currently available NK-targeted antitumor treatment strategies such as engineered viral vectors, small-molecule IMiDs, NK agonist antibodies, interleukins, and chimeric antigen receptor (CAR) NK cells, and their potential for improving the efficacy of immunotherapy in the treatment of bladder cancer.
    METHODS: Through review of current literature, we summarized our knowledge of NK cells in solid tumors and hematologic malignancies as their roles pertain to novel immunotherapies already being applied to the treatment of bladder cancer or that offer rationale for considering as potential novel immunotherapeutic strategies.
    RESULTS: NK cells play a critical role in shaping the tumor microenvironment (TME) that can be exploited to improve T cell-targeted immunotherapies.
    CONCLUSIONS: Emerging evidence suggests that NK cells are a prime target for improving antitumor functions in immunotherapies for the treatment of bladder cancer. Further research into profiling NK cells in settings of immunotherapies for bladder cancer could help identify patients who might maximally benefit from NK cell-targeted immunotherapies and the various approaches for exploiting their antitumor properties.
    Keywords:  Bladder cancer; NK cell; immunotherapy
    DOI:  https://doi.org/10.3233/BLC-220109
  27. J Gastrointest Oncol. 2024 Jun 30. 15(3): 1282-1296
    Lactic acid: a narrative review of a promoter of the liver cancer microenvironment.
    Junhe Chen, Guifang He, Duo Cai, Elisa Giovannetti, Kentaro Inamura, Shihai Liu, Wenzhe Ma.
      Background and Objective: Lactic acid is a metabolite of glycolysis produced in the body, and its production is thought to be a mechanism by which cancer cells evade immune surveillance. Immune evasion and metabolic changes are well established as basic hallmarks of cancer. Although lactate has long been considered a waste product, it is now generally recognized to be a versatile small-molecule chemical that plays an important part in the tumor microenvironment (TME), with increased lactate production linked to the development of human malignancies. Metabolism in liver cancer is redirected toward glycolysis, which enhances the production of metabolic compounds used by tumor cells to produce proteins, lipids, and nucleotides, enabling them to maintain high proliferation rates and to establish the TME. Dysregulation of metabolic activity in liver cancer may impair antitumor responses owing to the immunosuppressive activity of the lactate produced by anaerobic glycolytic rates in tumor cells. This review primarily explores the link connection between lactic acid and the TME; evaluates the role of lactic acid in the occurrence, metastasis, prognosis, and treatment of liver cancer. Additionally, it investigates the associated pathways as potential targets for liver cancer treatment.Methods: Literature searches were conducted in PubMed, Web of Science, and Google Scholar, with the publication date of the most recent article included being January 2024. After eliminating duplicate articles and less relevant articles through titles and abstracts, we selected 113 articles for this review. We categorized references into two categories. One is to classify the content into lactate-related, liver cancer-related and tumor metabolism-related. The other is to classify the article types, which are divided into reviews, research articles and clinical trials. Additionally, we consulted the reference lists of the relevant articles to ensure coverage was comprehensive and unbiased.
    Key Content and Findings: The connection between lactic acid and the TME has recently become an area of intense research interest, and many related articles have been published in this field. The main finding of this review is to summarize the proven link between lactate and the TME and its possible impact on the TME of liver cancer. And analyzed the potential of lactate in liver cancer treatment and prognosis prediction.
    Conclusions: Lactate may be key to developing novel approaches in the future treatment of liver cancer. Related research on the combination of classic therapies and molecular targeted drugs may provide innovative medicines that more selectively regulate immune cell activity.
    Keywords:  Lactic acid; cancer metabolism; immune cells; liver cancer; tumor microenvironment (TME)
    DOI:  https://doi.org/10.21037/jgo-24-368
  28. Biochim Biophys Acta Mol Basis Dis. 2024 Jul 09. pii: S0925-4439(24)00338-7. [Epub ahead of print] 167345
    Host derived macrophage migration inhibitory factor expression attenuates anti-tumoral immune cell accumulation and promotes immunosuppression in the tumor microenvironment of head and neck squamous cell carcinoma.
    Nathan Ryan, Felipe Lamenza, Suvekshya Shrestha, Puja Upadhaya, Anna Springer, Pete Jordanides, Hasan Pracha, Peyton Roth, Rathan Kumar, Yinchong Wang, Anna E Vilgelm, Abhay Satoskar, Steve Oghumu.
      Head and neck squamous cell carcinoma (HNSCC) is a significant public health concern worldwide. Immunomodulatory targets in the HNSCC tumor microenvironment are crucial to enhance the efficacy of HNSCC immunotherapy. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that has been linked to poor prognosis in many cancers, but the mechanistic role of MIF in HNSCC remains unclear. Using a murine orthotopic oral cancer model in Mif+/+ or Mif-/- mice, we determined the function of host derived MIF in HNSCC tumor development, metastasis as well as localized and systemic tumor immune responses. We observed that Mif-/- mice have decreased tumor growth and tumor burden compared to their wild-type counterparts. Flow cytometric analysis of immune populations within the primary tumor site revealed increased Th1 and cytotoxic T cell recruitment to the HNSCC tumor microenvironment. Within the tumors of Mif-/- mice, MIF deletion also enhanced the effector function of anti-tumoral effector CD8+ T cells as well as Th1 cells and decreased the accumulation of granulocytic myeloid derived suppressor cells (g-MDSCs) in the tumor microenvironment. Furthermore, MDSCs isolated from tumor bearing mice chemotactically respond to MIF in a dose dependent manner. Taken together, our results demonstrate a chemotactic and immunomodulatory role for host derived MIF in promoting HNSCC and suggest that MIF targeted immunomodulation is a promising approach for HNSCC treatment.
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167345
  29. J Stomatol Oral Maxillofac Surg. 2024 Jul 04. pii: S2468-7855(24)00210-6. [Epub ahead of print] 101964
    Extracellular vesicles in oral oncology: Interplay between the tumor microenvironment and disease progression.
    Rekha Thiruvengadam, Muthu Thiruvengadam.
      
    DOI:  https://doi.org/10.1016/j.jormas.2024.101964
  30. bioRxiv. 2024 Jun 28. pii: 2024.06.24.600383. [Epub ahead of print]
    Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors.
    Samarth Hegde, Bruno Giotti, Brian Y Soong, Laszlo Halasz, Jessica Le Berichel, Assaf Magen, Benoit Kloeckner, Raphaël Mattiuz, Matthew D Park, Adam Marks, Meriem Belabed, Pauline Hamon, Theodore Chin, Leanna Troncoso, Juliana J Lee, Dughan Ahimovic, Michael Bale, Grace Chung, Darwin D'souza, Krista Angeliadis, Travis Dawson, Seunghee Kim-Schulze, Raja M Flores, Andrew J Kaufman, Florent Ginhoux, Steven Z Josefowicz, Sai Ma, Alexander M Tsankov, Thomas U Marron, Brian D Brown, Miriam Merad.
      Monocyte-derived macrophages (mo-macs) drive immunosuppression in the tumor microenvironment (TME) and tumor-enhanced myelopoiesis in the bone marrow (BM) fuels these populations. Here, we performed paired transcriptome and chromatin analysis over the continuum of BM myeloid progenitors, circulating monocytes, and tumor-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. Analyzing chromatin accessibility and histone mark changes, we show that lung tumors prime accessibility for Nfe2l2 (NRF2) in BM myeloid progenitors as a cytoprotective response to oxidative stress. NRF2 activity is sustained and increased during monocyte differentiation into mo-macs in the lung TME to regulate oxidative stress, in turn promoting metabolic adaptation, resistance to cell death, and contributing to immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced mo-macs' survival and immunosuppression in the TME, enabling NK and T cell therapeutic antitumor immunity and synergizing with checkpoint blockade strategies. Altogether, our study identifies a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the TME.
    DOI:  https://doi.org/10.1101/2024.06.24.600383
  31. Nat Commun. 2024 Jul 10. 15(1): 5291
    TSG-6+ cancer-associated fibroblasts modulate myeloid cell responses and impair anti-tumor response to immune checkpoint therapy in pancreatic cancer.
    Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra, Padmanee Sharma.
      Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. TSG-6 inhibition in combination with ICT improves therapy response and survival in pancreatic tumor-bearing mice by reducing macrophages expressing immunosuppressive phenotypes and increasing CD8 T cells. Overall, our findings propose TSG-6 as a therapeutic target to enhance ICT response in non-responsive tumors.
    DOI:  https://doi.org/10.1038/s41467-024-49189-x
  32. Leuk Lymphoma. 2024 Jul 09. 1-17
    CD36: a promising therapeutic target in hematologic tumors.
    Ningning Yue, Qiqi Jin, Cuicui Li, Litian Zhang, Jiajia Cao, Chongyang Wu.
      Cluster of differentiation 36 (CD36) is a multiligand receptor with important roles in lipid metabolism, angiogenesis and innate immunity, and its diverse effects may depend on the binding of specific ligands in different contexts. CD36 is expressed not only on immune cells in the tumor microenvironment (TME) but also on some hematopoietic cells. CD36 is associated with the growth, metastasis and drug resistance in some hematologic tumors, such as leukemia, lymphoma and myelodysplastic syndrome. Currently, some targeted therapeutic agents against CD36 have been developed, such as anti-CD36 antibodies, CD36 antagonists (small molecules) and CD36 expression inhibitors. This paper not only innovatively addresses the role of CD36 in some hematopoietic cells, such as erythrocytes, hematopoietic stem cells and platelets, but also pays special attention to the role of CD36 in the development of hematologic tumors, and suggests that CD36 may be a potential cancer therapeutic target in hematologic tumors.
    Keywords:  CD36; hematologic tumors; therapeutic target
    DOI:  https://doi.org/10.1080/10428194.2024.2376178
  33. Cancer Immunol Res. 2024 Jul 11.
    The E3 ubiquitin ligase FBXO38 maintains the antitumor function of natural killer cells by sustaining IL-15R signaling.
    Yongjing Shi, Xiaodong Zheng, Hui Peng, Chenqi Xu, Rui Sun, Zhigang Tian, Haoyu Sun, Xianwei Wang.
      Natural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment (TME). It has been reported that the E3 ligase FBXO38 accelerates PD-1 degradation in tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that the transcriptional levels of FBXO38 in intratumoral NK cells of cancer patients and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knock-out (cKO) of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. FBXO38 deficiency resulted in impaired proliferation and survival of tumor-infiltrating NK (TINK) cells. Mechanistically, FBXO38 deficiency enhanced TGF-β signaling, including elevating expression of Smad2 and Smad3, which suppressed expression of the transcription factor Eomes and further reduced expression of surface IL-15Rβ and IL-15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL-15. Consistent with these observations, FBXO38 mRNA expression was positively correlated with the proliferation of TINK cells in multiple human tumors. To study the therapeutic potential of FBXO38, mice bearing human tumors were treated with FBXO38 overexpressed human primary NK cells and showed a significant reduction in tumor size and prolonged survival. In conclusion, our results suggest that FBXO38 sustains NK-cell expansion and survival to promote antitumor immunity, and have potential therapeutic implications as they suggest FBXO38 could be harnessed to enhance NK cell-based cancer immunotherapy.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-1061
  34. Int J Mol Sci. 2024 Jun 22. pii: 6868. [Epub ahead of print]25(13):
    Role of Protein Phosphatases in Tumor Angiogenesis: Assessing PP1, PP2A, PP2B and PTPs Activity.
    Márton Fonódi, Lilla Nagy, Anita Boratkó.
      Tumor angiogenesis, the formation of new blood vessels to support tumor growth and metastasis, is a complex process regulated by a multitude of signaling pathways. Dysregulation of signaling pathways involving protein kinases has been extensively studied, but the role of protein phosphatases in angiogenesis within the tumor microenvironment remains less explored. However, among angiogenic pathways, protein phosphatases play critical roles in modulating signaling cascades. This review provides a comprehensive overview of the involvement of protein phosphatases in tumor angiogenesis, highlighting their diverse functions and mechanisms of action. Protein phosphatases are key regulators of cellular signaling pathways by catalyzing the dephosphorylation of proteins, thereby modulating their activity and function. This review aims to assess the activity of the protein tyrosine phosphatases and serine/threonine phosphatases. These phosphatases exert their effects on angiogenic signaling pathways through various mechanisms, including direct dephosphorylation of angiogenic receptors and downstream signaling molecules. Moreover, protein phosphatases also crosstalk with other signaling pathways involved in angiogenesis, further emphasizing their significance in regulating tumor vascularization, including endothelial cell survival, sprouting, and vessel maturation. In conclusion, this review underscores the pivotal role of protein phosphatases in tumor angiogenesis and accentuate their potential as therapeutic targets for anti-angiogenic therapy in cancer.
    Keywords:  Ser/Thr phosphatases; Tyr phosphatases; endothelial cells; protein phosphatases; signaling pathways; tumor angiogenesis; tumor cells
    DOI:  https://doi.org/10.3390/ijms25136868
  35. Vascul Pharmacol. 2024 Jun;pii: S1537-1891(24)00036-3. [Epub ahead of print]155 107311
    Modulation of purinergic signaling in endothelial cells by tumor microenvironment.
    Giorgia Chinigò, Giorgia Scarpellino, Sara Petrillo, Tullio Genova, Federico Alessandro Ruffinatti, Luca Munaron.
      Purinergic signaling plays a crucial role in vascular endothelium functions. In particular, ionotropic P2X receptors (P2XRs) are engaged in various intracellular pathways through which endothelial cells (ECs) adapt to external stimuli. However, very little is known about the impact of P2XRs on vascular remodeling during carcinogenesis. We previously demonstrated that high purinergic stimulation impairs the migratory phenotype of tumor-derived endothelial cells (TECs) but not of normal ECs. Since P2XRs are sensitive to different physical and chemical factors, we investigated the impact of tumor microenvironment (TME) on healthy ECs to verify the ability of cancer cells to affect endothelial migratory phenotype through purinergic signaling tuning. More specifically, we focused on P2XR modulation by two different types of TME, mimicking breast and pancreas cancer milieux, which show very different features in terms of vascularization and composition. ECs conditioning with both cancer cell types induced a significant upregulation of some of the most represented P2XR. However, only conditioning with MCF-7 cells and not that with PANC-1 cells was able to alter the migratory phenotype of normal ECs supporting a P2XR-mediated inhibition of cell migration. The differences observed between the two cancer cells could be due to their different proliferative potential and the subsequent different extracellular pH. In addition, in agreement with some of our previous data, the P2XR-induced inhibition of EC migration seems to be independent of calcium signals, as conditioned ECs didn't reveal any changes in the long-lasting responses evoked by purinergic agonists. Collectively, highlighting a significant P2RX modulation by TME, our data strengthen the hypothesis that purinergic signaling may play a central role in vascular remodeling during carcinogenesis. However, the molecular routes upstream and downstream of this modulation remain to be elucidated.
    DOI:  https://doi.org/10.1016/j.vph.2024.107311
  36. Cell Death Discov. 2024 Jul 10. 10(1): 318
    Emerging roles of CAR-NK cell therapies in tumor immunotherapy: current status and future directions.
    Yan Zhong, Jingfeng Liu.
      Cancer immunotherapy harnesses the body's immune system to combat malignancies, building upon an understanding of tumor immunosurveillance and immune evasion mechanisms. This therapeutic approach reactivates anti-tumor immune responses and can be categorized into active, passive, and combined immunization strategies. Active immunotherapy engages the immune system to recognize and attack tumor cells by leveraging host immunity with cytokine supplementation or vaccination. Conversely, passive immunotherapy employs exogenous agents, such as monoclonal antibodies (anti-CTLA4, anti-PD1, anti-PD-L1) or adoptive cell transfers (ACT) with genetically engineered chimeric antigen receptor (CAR) T or NK cells, to exert anti-tumor effects. Over the past decades, CAR-T cell therapies have gained significant traction in oncological treatment, offering hope through their targeted approach. However, the potential adverse effects associated with CAR-T cells, including cytokine release syndrome (CRS), off-tumor toxicity, and neurotoxicity, warrant careful consideration. Recently, CAR-NK cell therapy has emerged as a promising alternative in the landscape of tumor immunotherapy, distinguished by its innate advantages over CAR-T cell modalities. In this review, we will synthesize the latest research and clinical advancements in CAR-NK cell therapies. We will elucidate the therapeutic benefits of employing CAR-NK cells in oncology and critically examine the developmental bottlenecks impeding their broader application. Our discussion aims to provide a comprehensive overview of the current status and future potential of CAR-NK cells in cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41420-024-02077-1
  37. Curr Neuropharmacol. 2024 Jul 10.
    Myeloid-derived Suppressor Cells and Multiple Sclerosis.
    Aurora Zanghì, Paola Sofia Di Filippo, Carlo Avolio, Emanuele D'Amico.
      Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous population of immature myeloid cells that play important roles in maintaining immune homeostasis and regulating immune responses. MDSCs can be divided into two main subsets based on their surface markers and functional properties: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs). Recently greatest attention has been paid to innate immunity in Multiple Sclerosis (MS), so the aim of our review is to provide an overview of the main characteristics of MDSCs in MS and its preclinical model by discussing the most recent data available. The immunosuppressive functions of MDSCs can be dysregulated in MS, leading to an exacerbation of the autoimmune response and disease progression. Antigen-specific peptide immunotherapy, which aims to restore tolerance while avoiding the use of non-specific immunosuppressive drugs, is a promising approach for autoimmune diseases, but the cellular mechanisms behind successful therapy remain poorly understood. Therefore, targeting MDSCs could be a promising therapeutic approach for MS. Various strategies for modulating MDSCs have been investigated, including the use of pharmacological agents, biological agents, and adoptive transfer of exogenous MDSCs. However, it remained unclear whether MDSCs display any therapeutic potential in MS and how this therapy could modulate different aspects of the disease. Collectively, all the described studies revealed a pivotal role for MDSCs in the regulation of MS.</p>.
    Keywords:  G-MDSCs; M-MDSCs; Multiple sclerosis; immune responses; myeloid-derived suppressor cells; therapeutic strategies
    DOI:  https://doi.org/10.2174/1570159X22999240710142942
  38. J Nanobiotechnology. 2024 Jul 08. 22(1): 400
    Reactive oxygen species/glutathione dual sensitive nanoparticles with encapsulation of miR155 and curcumin for synergized cancer immunotherapy.
    Kangkang Li, Juan Wang, Yi Xie, Ziyao Lu, Wen Sun, Kaixuan Wang, Jinxin Liang, Xuehong Chen.
      Considerable attention has been directed towards exploring the potential efficacy of miR-155 in the realm of cancer immunotherapy. Elevated levels of miR-155 in dendritic cells (DCs) have been shown to enhance their maturation, migration, cytokine secretion, and their ability to promote T cell activation. In addition, overexpression of mir155 in M2 macrophages boost the polarization towards the M1 phenotype. Conversely, miR-155 has the propensity to induce the accumulation of immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in the tumor tissue. To account for this discrepancy, it is imperative to get help from a drug that could deal with immunosuppressive effect. Curcumin (CUR) exhibits the capacity to prompt Tregs converse into T helper 1 cells, fostering the polarization of M2 tumor-associated macrophage towards the M1 phenotype, and impeding the recruitment and aggregation of MDSCs within the tumor microenvironment. Nonetheless, CUR is known to exert an immunosuppressive impact on DCs by hindering the expression of maturation markers, cytokines, and chemokines, thereby prevent DCs response to immunostimulatory agents. Hence, a reactive oxygen species/glutathione dual responsive drug conveyance platform (CUR/miR155@DssD-Hb NPs) was devised to co-deliver CUR and miR155, with the aim of exploring their synergistic potential in bolstering a sustained and robust anti-tumor immune response. In vitro and in vivo results have suggested that CUR/miR155@DssD-Hb NPs can effectively inhibit the viability of 4T1 and B16F10 tumor cells, trigger the release of damage associated molecular patterns, stimulate DCs maturation, subsequent activation of CD8+ T cells, diminish immunosuppressive cell populations (MDSCs, Tregs, M2 TAMs and exhausted T cells), promote the formation of long-term immunity and lessen the formation of metastatic nodules in the lungs. In summary, the co-delivery system integrating CUR and miR155 (CUR/miR155@DssD-Hb NPs) demonstrates promise as a promising strategy for the immunotherapy of melanoma and triple negative breast cancer.
    Keywords:  Curcumin; Immunotherapy; Melanoma; Triple negative breast cancer; miR155
    DOI:  https://doi.org/10.1186/s12951-024-02575-5
  39. Front Immunol. 2024 ;15 1394420
    The effect of exercise and disease status on mobilization of anti-tumorigenic and pro-tumorigenic immune cells in women with breast cancer.
    Tiia Koivula, Salla Lempiäinen, Joona Neuvonen, Jooa Norha, Maija Hollmén, Carl Johan Sundberg, Helene Rundqvist, Heikki Minn, Petteri Rinne, Ilkka Heinonen.
      Background: Mobilization of certain immune cells may improve the ability of the immune system to combat tumor cells, but the effect of acute exercise on mobilizing immune cells has been sparsely investigated in cancer patients. Therefore, we examined how acute exercise influences circulating immune cells in breast cancer patients.Methods: Nineteen newly diagnosed breast cancer patients aged 36-68 performed 30 minutes of moderate-intensity exercise with a cycle ergometer. Blood samples were collected at various time points: at rest, at 15 (E15) and 30 minutes (E30) after onset of the exercise, and at 30 and 60 minutes post-exercise. We analyzed several immune cell subsets using flow cytometry.
    Results: Acute exercise increased the number of total leukocytes, neutrophils, lymphocytes, monocytes, basophils, total T-cells, CD4+ T-cells, T helper (Th) 2-cells, Th 17-cells, CD8+ T-cells, CD4-CD8- T-cells, CD56+ natural killer (NK) cells, and CD14-CD16+ monocytes. Many of the changes were transient. Proportions of NK-cells and CD8+ T-cells increased, while the proportion of myeloid derived suppressor cells (MDSCs) reduced, and proportion of regulatory T-cells remained unchanged by exercise. Several associations were detected between cell mobilizations and disease state. For instance, tumor size correlated negatively with NK cell mobilization at E15, and progesterone receptor positivity correlated negatively with CD8+ T-cell mobilization.
    Conclusion: The findings show that the proportions of CD8+ T-cells and NK cells increased and the proportion of MDSCs proportion decreased in breast cancer patients after 30-minute exercise, suggesting a change in the profile of circulating immune cells towards more cytotoxic/anti-tumorigenic. The mobilization of some immune cells also appears to be related to the disease state.
    Keywords:  acute exercise; breast cancer; immune cell; immunity; physical activity; white blood cell
    DOI:  https://doi.org/10.3389/fimmu.2024.1394420
  40. bioRxiv. 2024 Jun 28. pii: 2024.06.25.600684. [Epub ahead of print]
    Medulloblastoma Spatial Transcriptomics Reveals Tumor Microenvironment Heterogeneity with High-Density Progenitor Cell Regions Correlating with High-Risk Disease.
    Franklin Chien, Marina E Michaud, Mojtaba Bakhtiari, Chanel Schroff, Matija Snuderl, Jose E Velazquez Vega, Tobey J MacDonald, Manoj K Bhasin.
      The tumor microenvironment (TME) of medulloblastoma (MB) influences progression and therapy response, presenting a promising target for therapeutic advances. Prior single-cell analyses have characterized the cellular components of the TME but lack spatial context. To address this, we performed spatial transcriptomic sequencing on sixteen pediatric MB samples obtained at diagnosis, including two matched diagnosis-relapse pairs. Our analyses revealed inter- and intra-tumoral heterogeneity within the TME, comprised of tumor-associated astrocytes (TAAs), macrophages (TAMs), stromal components, and distinct subpopulations of MB cells at different stages of neuronal differentiation and cell cycle progression. We identified dense regions of quiescent progenitor-like MB cells enriched in patients with high-risk (HR) features and an increase in TAAs, TAMs, and dysregulated vascular endothelium following relapse. Our study presents novel insights into the spatial architecture and cellular landscape of the medulloblastoma TME, highlighting spatial patterns linked to HR features and relapse, which may serve as potential therapeutic targets.
    DOI:  https://doi.org/10.1101/2024.06.25.600684
  41. Int J Mol Sci. 2024 Jun 28. pii: 7133. [Epub ahead of print]25(13):
    Mesenchymal Stem Cell-Secreted Exosomes and Soluble Signals Regulate Breast Cancer Metastatic Dormancy: Current Progress and Future Outlook.
    Bei Dai, Amanda M Clark, Alan Wells.
      Breast cancer is most common in women, and in most cases there is no evidence of spread and the primary tumor is removed, resulting in a 'cure'. However, in 10% to 30% of these women, distant metastases recur after years to decades. This is due to breast cancer cells disseminating to distant organs and lying quiescent. This is called metastatic dormancy. Dormant cells are generally resistant to chemotherapy, hormone therapy and immunotherapy as they are non-cycling and receive survival signals from their microenvironment. In this state, they are clinically irrelevant. However, risk factors, including aging and inflammation can awaken dormant cells and cause breast cancer recurrences, which may happen even more than ten years after the primary tumor removal. How these breast cancer cells remain in dormancy is being unraveled. A key element appears to be the mesenchymal stem cells in the bone marrow that have been shown to promote breast cancer metastatic dormancy in recent studies. Indirect co-culture, direct co-culture and exosome extraction were conducted to investigate the modes of signal operation. Multiple signaling molecules act in this process including both protein factors and microRNAs. We integrate these studies to summarize current findings and gaps in the field and suggest future research directions for this field.
    Keywords:  mesenchymal stem cells; metastatic breast cancer; metastatic dormancy; secretome
    DOI:  https://doi.org/10.3390/ijms25137133
  42. World J Urol. 2024 Jul 10. 42(1): 401
    Gender difference of bladder cancer: insights from hormone, anatomy and tumor microenvironment.
    Yuxuan Song, Tao Xu.
      
    DOI:  https://doi.org/10.1007/s00345-024-05091-1
  43. Cells. 2024 Jun 23. pii: 1087. [Epub ahead of print]13(13):
    Tumor Dormancy and Reactivation: The Role of Heat Shock Proteins.
    Haneef Ahmed Amissah, Stephanie E Combs, Maxim Shevtsov.
      Tumors are a heterogeneous group of cell masses originating in various organs or tissues. The cellular composition of the tumor cell mass interacts in an intricate manner, influenced by humoral, genetic, molecular, and tumor microenvironment cues that dictate tumor growth or suppression. As a result, tumors undergo a period of a dormant state before their clinically discernible stage, which surpasses the clinical dormancy threshold. Moreover, as a genetically imprinted strategy, early-seeder cells, a distinct population of tumor cells, break off to dock nearby or extravasate into blood vessels to secondary tissues, where they form disseminated solitary dormant tumor cells with reversible capacity. Among the various mechanisms underlying the dormant tumor mass and dormant tumor cell formation, heat shock proteins (HSPs) might play one of the most important roles in how the dormancy program plays out. It is known that numerous aberrant cellular processes, such as malignant transformation, cancer cell stemness, tumor invasion, metastasis, angiogenesis, and signaling pathway maintenance, are influenced by the HSPs. An accumulating body of knowledge suggests that HSPs may be involved in the angiogenic switch, immune editing, and extracellular matrix (ECM) remodeling cascades, crucial genetically imprinted strategies important to the tumor dormancy initiation and dormancy maintenance program. In this review, we highlight the biological events that orchestrate the dormancy state and the body of work that has been conducted on the dynamics of HSPs in a tumor mass, as well as tumor cell dormancy and reactivation. Additionally, we propose a conceptual framework that could possibly underlie dormant tumor reactivation in metastatic relapse.
    Keywords:  dormant tumor; dormant tumor cell; dormant tumor cell reactivation; extracellular matrix; heat shock proteins; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells13131087
  44. Int J Cancer. 2024 Jul 08.
    Pantoprazole and riluzole target H+/K+-ATPases and pH-sensitive K+ channels in pancreatic cancer cells.
    Ganga Deshar, Nynne M Christensen, Ivana Novak.
      Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer type. PDAC is characterized by fibrotic, hypoxic, and presumably acidic tumor microenvironment (TME). Acidic TME is an important player in tumor development, progression, aggressiveness, and chemoresistance. The dysregulation of ductal ion transporters/channels might contribute to extracellular pH (pHe) acidification and PDAC progression. Our aim was to test whether H+/K+-ATPases and pH-sensitive K+ channels contribute to these processes and could be targeted by clinically approved drugs. We used human pancreatic cancer cells adapted to various pHe conditions and grown in monolayers and spheroids. First, we created cells expressing pHoran4 at the outer plasma membrane and showed that pantoprazole, the H+/K+-ATPase inhibitor, alkalinized pHe. Second, we used FluoVolt to monitor the membrane voltage (Vm) and showed that riluzole hyperpolarized Vm, most likely by opening of pH-sensitive K+ channels such as TREK-1. Third, we show that pantoprazole and riluzole inhibited cell proliferation and viability of monolayers and spheroids of cancer cells adapted to various pHe conditions. Most importantly, combination of the two drugs had significantly larger inhibitory effects on PDAC cell survival. We propose that co-targeting H+/K+-ATPases and pH-sensitive K+ channels by re-purposing of pantoprazole and riluzole could provide novel acidosis-targeted therapies of PDAC.
    Keywords:  BL 1249; K2P channels; PPIs; TREK‐1; extracellular pH sensor; proton pump inhibitors; spheroids; tumor microenvironment
    DOI:  https://doi.org/10.1002/ijc.35076
  45. Cytoskeleton (Hoboken). 2024 Jul 09.
    Enhanced RHO-ROCK signaling is associated with CRELD2 production and fibroblast recruitment in cutaneous squamous cell carcinoma.
    Alexandra Pittar, Edward J Buckley, Sarah T Boyle, S Jan Ibbetson, Michael S Samuel.
      A key characteristic of cancer cells is their ability to induce changes in their microenvironment that render it permissive to tumor growth, invasion and metastasis. Indeed, these changes are required for tumor progression. Consequently, the tumor microenvironment is emerging as a key source of new targets against cancer, with novel therapies aimed at reversing tumor-promoting changes, reinstating a tumor-hostile microenvironment and suppressing disease progression. RHO-ROCK signaling, and consequent tension within the cellular actomyosin cytoskeleton, regulates a paracrine signaling cascade that establishes a tumor-promoting microenvironment. Here, we show that consistent with our observations in breast cancer, enhanced ROCK activity and consequent production of CRELD2 is associated with the recruitment and tumor-promoting polarization of cancer-associated fibroblasts in cutaneous squamous cell carcinoma. Our observations provide support for the notion that the role of RHO-ROCK signaling in establishing a tumor-promoting microenvironment may be conserved across patients and potentially also different cancer types.
    Keywords:  CRELD2; RHO‐ROCK signaling; cancer‐associated fibroblasts; cutaneous squamous cell carcinoma; extracellular matrix
    DOI:  https://doi.org/10.1002/cm.21894
  46. J Immunother Cancer. 2024 Jul 08. pii: e009595. [Epub ahead of print]12(7):
    Hypothesis: the generation of T cells directed against neoepitopes employing immune-mediating agents other than neoepitope vaccines.
    Jeffrey Schlom, Renee N Donahue, Claudia Palena, Sofia R Gameiro, James W Hodge, Duane H Hamilton, James L Gulley.
      The development of vaccines, especially RNA-based, directed against patient-specific tumor neoepitopes is an active and productive area of cancer immunotherapy. Promising clinical results in melanoma and other solid tumor types are emerging. As with all cancer therapy modalities, neoepitope vaccine development and delivery also has some drawbacks, including the level of effort to develop a patient-specific product, accuracy of algorithms to predict neoepitopes, and with the exception of melanoma and some other tumor types, biopsies of metastatic lesions of solid tumors are often not available. We hypothesize that in some circumstances the use of rationally designed combinations of "off-the-shelf" agents may prove an additional path to enable the patient to produce his/her own "neoepitope vaccine" in situ. These combination therapies may consist of agents to activate a tumor-associated T-cell response, potentiate that response, reduce or eliminate immunosuppressive entities in the tumor microenvironment, and/or alter the phenotype of tumor cells to render them more susceptible to immune-mediated lysis. Examples are provided in both preclinical and clinical studies in which combinations of "off-the-shelf" agents lead to the generation of T cells directed against tumor-derived neoepitopes with consequent antitumor activity.
    Keywords:  Combination therapy; Immune modulatory; Immunotherapy; Vaccine
    DOI:  https://doi.org/10.1136/jitc-2024-009595
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