bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–03–10
27 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. CAFs vs. TECs: when blood feuds fuel cancer progression, dissemination and therapeutic resistance.
  2. Inflammation and tumor microenvironment.
  3. Editorial: Spatial immune cell heterogeneity in the tumor microenvironment.
  4. Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment.
  5. Immunometabolic Maladaptations to the Tumor Microenvironment.
  6. Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy.
  7. Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment.
  8. Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy.
  9. Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy.
  10. The effects of metabolism on the immune microenvironment in colorectal cancer.
  11. Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy.
  12. Advances in cancer mechanobiology: Metastasis, mechanics, and materials.
  13. Rebuilding the microenvironment of primary tumors in humans: a focus on stroma.
  14. Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy.
  15. Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point?
  16. Targeting MHC-I inhibitory pathways for cancer immunotherapy.
  17. Targeting the innate immune system in pediatric and adult AML.
  18. Hybrid Cellular Nanovesicles Block PD-L1 Signal and Repolarize M2 Macrophages for Cancer Immunotherapy.
  19. Progress in research on the role played by myeloid-derived suppressor cells in liver diseases.
  20. Epigenetic regulation of tumor-immune symbiosis in glioma.
  21. A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
  22. An oncolytic vaccinia virus encoding hyaluronidase reshapes the extracellular matrix to enhance cancer chemotherapy and immunotherapy.
  23. Hypoxia effects on glioblastoma progression through YAP/TAZ pathway regulation.
  24. The potential of aryl hydrocarbon receptor as receptors for metabolic changes in tumors.
  25. Translational adaptation in breast cancer metastasis and emerging therapeutic opportunities.
  26. Neutrophils in the tumor microenvironment - when a company becomes a crowd.
  27. Engagement of sialylated glycans with Siglec receptors on suppressive myeloid cells inhibits anticancer immunity via CCL2.
  1. Cell Oncol (Dordr). 2024 Mar 07.
    CAFs vs. TECs: when blood feuds fuel cancer progression, dissemination and therapeutic resistance.
    Diane Coursier, Fernando Calvo.
      Neoplastic progression involves complex interactions between cancer cells and the surrounding stromal milieu, fostering microenvironments that crucially drive tumor progression and dissemination. Of these stromal constituents, cancer-associated fibroblasts (CAFs) emerge as predominant inhabitants within the tumor microenvironment (TME), actively shaping multiple facets of tumorigenesis, including cancer cell proliferation, invasiveness, and immune evasion. Notably, CAFs also orchestrate the production of pro-angiogenic factors, fueling neovascularization to sustain the metabolic demands of proliferating cancer cells. Moreover, CAFs may also directly or indirectly affect endothelial cell behavior and vascular architecture, which may impact in tumor progression and responses to anti-cancer interventions. Conversely, tumor endothelial cells (TECs) exhibit a corrupted state that has been shown to affect cancer cell growth and inflammation. Both CAFs and TECs are emerging as pivotal regulators of the TME, engaging in multifaceted biological processes that significantly impact cancer progression, dissemination, and therapeutic responses. Yet, the intricate interplay between these stromal components and the orchestrated functions of each cell type remains incompletely elucidated. In this review, we summarize the current understanding of the dynamic interrelationships between CAFs and TECs, discussing the challenges and prospects for leveraging their interactions towards therapeutic advancements in cancer.
    Keywords:  CAFs; Cancer; Crosstalk; Endothelia; Signaling; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s13402-024-00931-z
  2. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2023 Dec 28. pii: 1672-7347(2023)12-1899-15. [Epub ahead of print]48(12): 1899-1913
    Inflammation and tumor microenvironment.
    Tao Niu, Fenghai Zhou.
      There is a connection between inflammation and cancer. Inflammation is one of the hallmarks of cancer, affecting tumor progression, transition to a malignant phenotype, and the efficacy of tumor chemotherapy. The tumor microenvironment impacts the biological characteristics of tumors through various specific factors and signaling mechanisms. The interaction between inflammation and the tumor microenvironment involves inflammation affecting the tumor microenvironment by inducing immune suppression, while acute inflammation promotes tumor suppression by producing anti-tumor immune responses. This review elaborates on how inflammation affects the tumor microenvironment and thus affects the progression and treatment of tumors, starting from the components of the tumor microenvironment, inflammasomes, cytokines, non-coding RNAs, and other aspects. Inflammatory factors play an important role in regulating inflammatory responses and immune reactions, and they also affect the development of tumors through various pathways in the tumor microenvironment. In addition, non-coding RNAs play an important role in the tumor microenvironment, regulating tumors and inflammation. They are involved in regulating the occurrence, development of tumors, the process of inflammation, as well as regulating inflammation-induced cancer or tumor-related inflammation, and the interaction between the tumor microenvironment, inflammatory factors, and immune cells. Therefore, gaining a deeper understanding of the interaction between inflammation and the tumor microenvironment and its connection to the occurrence and development of cancer can provide a theoretical basis for combating tumors and finding new therapeutic strategies.
    Keywords:  cyclic RNA; inflammation; tumor; tumor microenvironment
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2023.230231
  3. Front Immunol. 2024 ;15 1377532
    Editorial: Spatial immune cell heterogeneity in the tumor microenvironment.
    Anirban Ganguly, Sumit Mukherjee, Sheila Spada.
      
    Keywords:  CAR-T; cancer; immunotherapy; oncoimmunology; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1377532
  4. Front Immunol. 2024 ;15 1327281
    Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment.
    Yue Qiu, Guimei Lu, Na Li, Yanyan Hu, Hao Tan, Chengyao Jiang.
      Gastric cancer (GC) is a malignant neoplasm originating from the epithelial cells of the gastric mucosa. The pathogenesis of GC is intricately linked to the tumor microenvironment within which the cancer cells reside. Tumor-associated macrophages (TAMs) primarily differentiate from peripheral blood monocytes and can be broadly categorized into M1 and M2 subtypes. M2-type TAMs have been shown to promote tumor growth, tissue remodeling, and angiogenesis. Furthermore, they can actively suppress acquired immunity, leading to a poorer prognosis and reduced tolerance to chemotherapy. Exosomes, which contain a myriad of biologically active molecules including lipids, proteins, mRNA, and noncoding RNAs, have emerged as key mediators of communication between tumor cells and TAMs. The exchange of these molecules via exosomes can markedly influence the tumor microenvironment and consequently impact tumor progression. Recent studies have elucidated a correlation between TAMs and various clinicopathological parameters of GC, such as tumor size, differentiation, infiltration depth, lymph node metastasis, and TNM staging, highlighting the pivotal role of TAMs in GC development and metastasis. In this review, we aim to comprehensively examine the bidirectional communication between GC cells and TAMs, the implications of alterations in the tumor microenvironment on immune escape, invasion, and metastasis in GC, targeted therapeutic approaches for GC, and the efficacy of potential GC drug resistance strategies.
    Keywords:  exosome; gastric cancer (GC); immune; tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3389/fimmu.2024.1327281
  5. Cold Spring Harb Perspect Med. 2024 Mar 04. pii: a041547. [Epub ahead of print]
    Immunometabolic Maladaptations to the Tumor Microenvironment.
    Emma S Hathaway, Erin Q Jennings, Jeffrey C Rathmell.
      Tumors consist of cancer cells and a wide range of tissue resident and infiltrating cell types. Tumor metabolism, however, has largely been studied on whole tumors or cancer cells and the metabolism of infiltrating immune cells remains poorly understood. It is now clear from a range of analyses and metabolite rescue studies that metabolic adaptations to the tumor microenvironment (TME) directly impede T-cell and macrophage effector functions. The drivers of metabolic adaptation to the TME and metabolic immune suppression include depletion of essential nutrients, accumulation of waste products or immune suppression metabolites, and metabolic signaling through altered posttranslational modifications. Each infiltrating immune cell subset differs, however, with specific metabolic requirements and adaptations that can be maladaptive for antitumor immunity. Here, we review T-cell and macrophage adaptation and metabolic immune suppression in solid tumors. Ultimately, understanding and addressing these challenges will improve cancer immunotherapy and adoptive chimeric antigen receptor T-cell therapies.
    DOI:  https://doi.org/10.1101/cshperspect.a041547
  6. Front Mol Biosci. 2023 ;10 1297611
    Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy.
    Kangqi Yang, Tuo Yi.
      The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.
    Keywords:  cancer stem cell; cancer-associated fibroblast; epithelial-to-mesenchymal transition; gastrointestinal tumor; tumor heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fmolb.2023.1297611
  7. Immunol Rev. 2024 Mar 09.
    Metabolic adaptations determine whether natural killer cells fail or thrive within the tumor microenvironment.
    Adnan Moinuddin, Sophie M Poznanski, Ana L Portillo, Jonathan K Monteiro, Ali A Ashkar.
      Natural Killer (NK) cells are a top contender in the development of adoptive cell therapies for cancer due to their diverse antitumor functions and ability to restrict their activation against nonmalignant cells. Despite their success in hematologic malignancies, NK cell-based therapies have been limited in the context of solid tumors. Tumor cells undergo various metabolic adaptations to sustain the immense energy demands that are needed to support their rapid and uncontrolled proliferation. As a result, the tumor microenvironment (TME) is depleted of nutrients needed to fuel immune cell activity and contains several immunosuppressive metabolites that hinder NK cell antitumor functions. Further, we now know that NK cell metabolic status is a main determining factor of their effector functions. Hence, the ability of NK cells to withstand and adapt to these metabolically hostile conditions is imperative for effective and sustained antitumor activity in the TME. With this in mind, we review the consequences of metabolic hostility in the TME on NK cell metabolism and function. We also discuss tumor-like metabolic programs in NK cell induced by STAT3-mediated expansion that adapt NK cells to thrive in the TME. Finally, we examine how other approaches can be applied to enhance NK cell metabolism in tumors.
    Keywords:  cancer immunotherapy; immunometabolism; metabolic reprogramming; natural killer cells; tumor metabolism
    DOI:  https://doi.org/10.1111/imr.13316
  8. Biochem Pharmacol. 2024 Feb 29. pii: S0006-2952(24)00081-9. [Epub ahead of print]222 116098
    Lactic acid in macrophage polarization: A factor in carcinogenesis and a promising target for cancer therapy.
    Mobarakeh Ajam-Hosseini, Romina Heydari, Milad Rasouli, Fatemeh Akhoondi, Niloofar Asadi Hanjani, Sander Bekeschus, Mohammad Doroudian.
      Cancer remains a formidable challenge, continually revealing its intricate nature and demanding novel treatment approaches. Within this intricate landscape, the tumor microenvironment and its dynamic components have gained prominence, particularly macrophages that can adopt diverse polarization states, exerting a profound influence on cancer progression. Recent revelations have spotlighted lactic acid as a pivotal player in this complex interplay. This review systematically explores lactic acid's multifaceted role in macrophage polarization, focusing on its implications in carcinogenesis. We commence by cultivating a comprehensive understanding of the tumor microenvironment and the pivotal roles played by macrophages. The dynamic landscape of macrophage polarization, typified by M1 and M2 phenotypes, is dissected to reveal its substantial impact on tumor progression. Lactic acid, a metabolic byproduct, emerges as a key protagonist, and we meticulously unravel the mechanisms underpinning its generation within cancer cells, shedding light on its intimate association with glycolysis and its transformative effects on the tumor microenvironment. Furthermore, we decipher the intricate molecular framework that underlies lactic acid's pivotal role in facilitating macrophage polarization. Our review underscores lactic acid's dual role in carcinogenesis, orchestrating tumor growth and immune modulation within the tumor microenvironment, thereby profoundly influencing the balance between pro-tumor and anti-tumor immune responses. This duality highlights the therapeutic potential of selectively manipulating lactic acid metabolism for cancer treatment. Exploring strategies to inhibit lactic acid production by tumor cells, novel approaches to impede lactic acid transport in the tumor microenvironment, and the burgeoning field of immunotherapeutic cancer therapies utilizing lactic acid-induced macrophage polarization form the core of our investigation.
    Keywords:  Blocking strategies; Cancer therapy; Lactic acid; Macrophage polarization; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bcp.2024.116098
  9. J Transl Med. 2024 Mar 03. 22(1): 229
    Advances in metabolic reprogramming of NK cells in the tumor microenvironment on the impact of NK therapy.
    Linxuan Miao, Chenglin Lu, Bin Zhang, Huili Li, Xu Zhao, Haoran Chen, Ying Liu, Xiaonan Cui.
      Natural killer (NK) cells are unique from other immune cells in that they can rapidly kill multiple neighboring cells without the need for antigenic pre-sensitization once the cells display surface markers associated with oncogenic transformation. Given the dynamic role of NK cells in tumor surveillance, NK cell-based immunotherapy is rapidly becoming a "new force" in tumor immunotherapy. However, challenges remain in the use of NK cell immunotherapy in the treatment of solid tumors. Many metabolic features of the tumor microenvironment (TME) of solid tumors, including oxygen and nutrient (e.g., glucose, amino acids) deprivation, accumulation of specific metabolites (e.g., lactate, adenosine), and limited availability of signaling molecules that allow for metabolic reorganization, multifactorial shaping of the immune-suppressing TME impairs tumor-infiltrating NK cell function. This becomes a key barrier limiting the success of NK cell immunotherapy in solid tumors. Restoration of endogenous NK cells in the TME or overt transfer of functionally improved NK cells holds great promise in cancer therapy. In this paper, we summarize the metabolic biology of NK cells, discuss the effects of TME on NK cell metabolism and effector functions, and review emerging strategies for targeting metabolism-improved NK cell immunotherapy in the TME to circumvent these barriers to achieve superior efficacy of NK cell immunotherapy.
    Keywords:  Immunotherapy; Natural killer cells; Solid tumors; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-024-05033-w
  10. Cell Death Discov. 2024 Mar 07. 10(1): 118
    The effects of metabolism on the immune microenvironment in colorectal cancer.
    Xingzhao Chen, Zhiyuan Ma, Zhiqiang Yi, Enqin Wu, Zhengye Shang, Biguang Tuo, Taolang Li, Xuemei Liu.
      Colorectal cancer (CRC) is a malignancy that is widely prevalent worldwide. Due to its unsatisfactory treatment outcome and extremely poor prognosis, many studies on the molecular mechanisms and pathological mechanisms of CRC have been published in recent years. The tumor microenvironment (TME) is an extremely important feature of tumorigenesis and one of the hallmarks of tumor development. Metabolic reprogramming is currently a hot topic in tumor research, and studies on this topic have provided important insights into CRC development. In particular, metabolic reprogramming in cancer causes changes in the composition of energy and nutrients in the TME. Furthermore, it can alter the complex crosstalk between immune cells and associated immune factors, such as associated macrophages and T cells, which play important immune roles in the TME, in turn affecting the immune escape of tumors by altering immune surveillance. In this review, we summarize several metabolism-related processes affecting the immune microenvironment of CRC tumors. Our results showed that the immune microenvironment is regulated by metabolic reprogramming and influences the development of CRC.
    DOI:  https://doi.org/10.1038/s41420-024-01865-z
  11. Front Immunol. 2024 ;15 1352484
    Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy.
    Man Wang, Fei Yu, Yuan Zhang, Peifeng Li.
      Notch signaling pathway is a highly conserved system of cell-to-cell communication that participates in various biological processes, such as stem cell maintenance, cell fate decision, cell proliferation and death during homeostasis and development. Dysregulation of Notch signaling has been associated with many aspects of cancer biology, such as maintenance of cancer stem-like cells (CSCs), cancer cell metabolism, angiogenesis and tumor immunity. Particularly, Notch signaling can regulate antitumor or pro-tumor immune cells within the tumor microenvironment (TME). Currently, Notch signaling has drawn significant attention in the therapeutic development of cancer treatment. In this review, we focus on the role of Notch signaling pathway in remodeling tumor immune microenvironment. We describe the impact of Notch signaling on the efficacy of cancer immunotherapies. Furthermore, we summarize the results of relevant preclinical and clinical trials of Notch-targeted therapeutics and discuss the challenges in their clinical application in cancer therapy. An improved understanding of the involvement of Notch signaling in tumor immunity will open the door to new options in cancer immunotherapy treatment.
    Keywords:  Notch signaling; Notch-targeted therapeutics; cancer development; cancer immunotherapy; tumor immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1352484
  12. APL Bioeng. 2024 Mar;8(1): 011502
    Advances in cancer mechanobiology: Metastasis, mechanics, and materials.
    Abigail J Clevenger, Maygan K McFarlin, John Paul M Gorley, Spencer C Solberg, Anirudh K Madyastha, Shreya A Raghavan.
      Within the tumor microenvironment (TME), tumor cells are exposed to numerous mechanical forces, both internally and externally, which contribute to the metastatic cascade. From the initial growth of the tumor to traveling through the vasculature and to the eventual colonization of distant organs, tumor cells are continuously interacting with their surroundings through physical contact and mechanical force application. The mechanical forces found in the TME can be simplified into three main categories: (i) shear stress, (ii) tension and strain, and (iii) solid stress and compression. Each force type can independently impact tumor growth and progression. Here, we review recent bioengineering strategies, which have been employed to establish the connection between mechanical forces and tumor progression. While many cancers are explored in this review, we place great emphasis on cancers that are understudied in their response to mechanical forces, such as ovarian and colorectal cancers. We discuss the major steps of metastatic transformation and present novel, recent advances in model systems used to study how mechanical forces impact the study of the metastatic cascade. We end by summarizing systems that incorporate multiple forces to expand the complexity of our understanding of how tumor cells sense and respond to mechanical forces in their environment. Future studies would also benefit from the inclusion of time or the aspect of mechanical memory to further enhance this field. While the knowledge of mechanical forces and tumor metastasis grows, developing novel materials and in vitro systems are essential to providing new insight into predicting, treating, and preventing cancer progression and metastasis.
    DOI:  https://doi.org/10.1063/5.0186042
  13. Exp Mol Med. 2024 Mar 05.
    Rebuilding the microenvironment of primary tumors in humans: a focus on stroma.
    Siwon Mun, Hyun Jin Lee, Pilnam Kim.
      Conventional tumor models have critical shortcomings in that they lack the complexity of the human stroma. The heterogeneous stroma is a central compartment of the tumor microenvironment (TME) that must be addressed in cancer research and precision medicine. To fully model the human tumor stroma, the deconstruction and reconstruction of tumor tissues have been suggested as new approaches for in vitro tumor modeling. In this review, we summarize the heterogeneity of tumor-associated stromal cells and general deconstruction approaches used to isolate patient-specific stromal cells from tumor tissue; we also address the effect of the deconstruction procedure on the characteristics of primary cells. Finally, perspectives on the future of reconstructed tumor models are discussed, with an emphasis on the essential prerequisites for developing authentic humanized tumor models.
    DOI:  https://doi.org/10.1038/s12276-024-01191-5
  14. Front Mol Biosci. 2024 ;11 1343523
    Dynamic interactions in the tumor niche: how the cross-talk between CAFs and the tumor microenvironment impacts resistance to therapy.
    Oliwia Piwocka, Igor Piotrowski, Wiktoria M Suchorska, Katarzyna Kulcenty.
      The tumor microenvironment (TME) is a complex ecosystem of cells, signaling molecules, and extracellular matrix components that profoundly influence cancer progression. Among the key players in the TME, cancer-associated fibroblasts (CAFs) have gained increasing attention for their diverse and influential roles. CAFs are activated fibroblasts found abundantly within the TME of various cancer types. CAFs contribute significantly to tumor progression by promoting angiogenesis, remodeling the extracellular matrix, and modulating immune cell infiltration. In order to influence the microenvironment, CAFs engage in cross-talk with immune cells, cancer cells, and other stromal components through paracrine signaling and direct cell-cell interactions. This cross-talk can result in immunosuppression, tumor cell proliferation, and epithelial-mesenchymal transition, contributing to disease progression. Emerging evidence suggests that CAFs play a crucial role in therapy resistance, including resistance to chemotherapy and radiotherapy. CAFs can modulate the tumor response to treatment by secreting factors that promote drug efflux, enhance DNA repair mechanisms, and suppress apoptosis pathways. This paper aims to understand the multifaceted functions of CAFs within the TME, discusses cross-talk between CAFs with other TME cells, and sheds light on the contibution of CAFs to therapy resistance. Targeting CAFs or disrupting their cross-talk with other cells holds promise for overcoming drug resistance and improving the treatment efficacy of various cancer types.
    Keywords:  cancer; cancer-associated fibroblasts; cross-talk; radiotherapy; therapy resistance; tumor-microenvironment
    DOI:  https://doi.org/10.3389/fmolb.2024.1343523
  15. Front Immunol. 2024 ;15 1345838
    Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point?
    Jinming Liu, Biao Zhang, Guolin Zhang, Dong Shang.
      Overcoming the immunosuppressive tumor microenvironment and identifying widely used immunosuppressants with minimal side effects are two major challenges currently hampering cancer immunotherapy. Regulatory T cells (Tregs) are present in almost all cancer tissues and play an important role in preserving autoimmune tolerance and tissue homeostasis. The tumor inflammatory microenvironment causes the reprogramming of Tregs, resulting in the conversion of Tregs to immunosuppressive phenotypes. This process ultimately facilitates tumor immune escape or tumor progression. However, current systemic Treg depletion therapies may lead to severe autoimmune toxicity. Therefore, it is crucial to understand the mechanism of Treg reprogramming and develop immunotherapies that selectively target Tregs within tumors. This article provides a comprehensive review of the potential mechanisms involved in Treg cell reprogramming and explores the application of Treg cell immunotherapy. The interference with reprogramming pathways has shown promise in reducing the number of tumor-associated Tregs or impairing their function during immunotherapy, thereby improving anti-tumor immune responses. Furthermore, a deeper understanding of the mechanisms that drive Treg cell reprogramming could reveal new molecular targets for future treatments.
    Keywords:  Foxp3; cancer therapy; metabolize; posttranslational modification; regulatory T cells; reprogramming; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2024.1345838
  16. Trends Immunol. 2024 Mar 02. pii: S1471-4906(24)00022-X. [Epub ahead of print]
    Targeting MHC-I inhibitory pathways for cancer immunotherapy.
    Jun Wang, Qiao Lu, Xufeng Chen, Iannis Aifantis.
      The MHC-I antigen presentation (AP) pathway is key to shaping mammalian CD8+ T cell immunity, with its aberrant expression closely linked to low tumor immunogenicity and immunotherapy resistance. While significant attention has been given to genetic mutations and downregulation of positive regulators that are essential for MHC-I AP, there is a growing interest in understanding how tumors actively evade MHC-I expression and/or AP through the induction of MHC-I inhibitory pathways. This emerging field of study may offer more viable therapeutic targets for future cancer immunotherapy. Here, we explore potential mechanisms by which cancer cells evade MHC-I AP and function and propose therapeutic strategies that might target these MHC-I inhibitors to restore impaired T cell immunity within the tumor microenvironment (TME).
    Keywords:  CD8 T cell; Immune inhibitory mechanisms; MHC-I; antigen presentation; cancer immune evasion; cancer immunotherapy
    DOI:  https://doi.org/10.1016/j.it.2024.01.009
  17. Leukemia. 2024 Mar 08.
    Targeting the innate immune system in pediatric and adult AML.
    Alicia Perzolli, Joost B Koedijk, C Michel Zwaan, Olaf Heidenreich.
      While the introduction of T cell-based immunotherapies has improved outcomes in many cancer types, the development of immunotherapies for both adult and pediatric AML has been relatively slow and limited. In addition to the need to identify suitable target antigens, a better understanding of the immunosuppressive tumor microenvironment is necessary for the design of novel immunotherapy approaches. To date, most immune characterization studies in AML have focused on T cells, while innate immune lineages such as monocytes, granulocytes and natural killer (NK) cells, received less attention. In solid cancers, studies have shown that innate immune cells, such as macrophages, myeloid-derived suppressor cells and neutrophils are highly plastic and may differentiate into immunosuppressive cells depending on signals received in their microenvironment, while NK cells appear to be functionally impaired. Hence, an in-depth characterization of the innate immune compartment in the TME is urgently needed to guide the development of immunotherapeutic interventions for AML. In this review, we summarize the current knowledge on the innate immune compartment in AML, and we discuss how targeting its components may enhance T cell-based- and other immunotherapeutic approaches.
    DOI:  https://doi.org/10.1038/s41375-024-02217-7
  18. Small. 2024 Mar 08. e2311702
    Hybrid Cellular Nanovesicles Block PD-L1 Signal and Repolarize M2 Macrophages for Cancer Immunotherapy.
    Chenchen Zhao, Yuanwei Pan, Lujie Liu, Jing Zhang, Xianjia Wu, Yu Liu, Xing-Zhong Zhao, Lang Rao.
      The PD1/PD-L1 immune checkpoint blocking is a promising therapy, while immunosuppressive tumor microenvironment (TME) and poor tumor penetration of therapeutic antibodies limit its efficacy. Repolarization of tumor-associated macrophages (TAMs) offers a potential method to ameliorate immunosuppression of TME and further boost T cell antitumor immunity. Herein, hybrid cell membrane biomimetic nanovesicles (hNVs) are developed by fusing M1 macrophage-derived nanovesicles (M1-NVs) and PD1-overexpressed tumor cell-derived nanovesicles (PD1-NVs) to improve cancer immunotherapy. The M1-NVs promote the transformation of M2-like TAMs to M1-like phenotype and further increase the release of pro-inflammatory cytokines, resulting in improved immunosuppressive TME. Concurrently, the PD1-NVs block PD1/PD-L1 pathway, which boosts cancer immunotherapy when combined with M1-NVs. In a breast cancer mouse model, the hNVs efficiently accumulate at the tumor site after intravenous injection and significantly inhibit the tumor growth. Mechanically, the M1 macrophages and CD8+ T lymphocytes in TME increase by twofold after the treatment, indicating effective immune activation. These results suggest the hNVs as a promising strategy to integrate TME improvement with PD1/PD-L1 blockade for cancer immunotherapy.
    Keywords:  biomimetic nanoparticles; cancer immunotherapy; cell membrane vesicles; immune checkpoint blockade; macrophage polarization
    DOI:  https://doi.org/10.1002/smll.202311702
  19. Scand J Immunol. 2023 Oct;98(4): e13312
    Progress in research on the role played by myeloid-derived suppressor cells in liver diseases.
    Qianqian Sun, Heng Dai, Siliang Wang, Yuanyuan Chen, Huilian Shi.
      Myeloid-derived suppressor cells (MDSCs) refer to a group of immature myeloid cells with potent immunosuppressive capacity upon activation by pathological conditions. Because of their potent immunosuppressive ability, MDSCs have garnered extensive attention in the past few years in the fields of oncology, infection, chronic inflammation and autoimmune diseases. Research on MDSCs in liver diseases has gradually increased, and their potential therapeutic roles will be further explored. This review presents a summary of the involvement and the role played by MDSCs in liver diseases, thus identifying their potential targets for the treatment of liver diseases and providing new directions for liver disease-related research.
    Keywords:  immunosuppression; immunotherapy; liver diseases; myeloid‐derived suppressor cells
    DOI:  https://doi.org/10.1111/sji.13312
  20. Trends Mol Med. 2024 Mar 06. pii: S1471-4914(24)00029-7. [Epub ahead of print]
    Epigenetic regulation of tumor-immune symbiosis in glioma.
    Yang Liu, Heba Ali, Fatima Khan, Lizhi Pang, Peiwen Chen.
      Glioma is a type of aggressive and incurable brain tumor. Patients with glioma are highly resistant to all types of therapies, including immunotherapies. Epigenetic reprogramming is a key molecular hallmark in tumors across cancer types, including glioma. Mounting evidence highlights a pivotal role of epigenetic regulation in shaping tumor biology and therapeutic responses through mechanisms involving both glioma cells and immune cells, as well as their symbiotic interactions in the tumor microenvironment (TME). In this review, we discuss the molecular mechanisms of epigenetic regulation that impacts glioma cell biology and tumor immunity in both a cell-autonomous and non-cell-autonomous manner. Moreover, we provide an overview of potential therapeutic approaches that can disrupt epigenetic-regulated tumor-immune symbiosis in the glioma TME.
    Keywords:  epigenetics; glioma; immunotherapy; therapeutic potential; tumor-immune symbiosis
    DOI:  https://doi.org/10.1016/j.molmed.2024.02.004
  21. J Exp Clin Cancer Res. 2024 Mar 08. 43(1): 74
    A glutamine tug-of-war between cancer and immune cells: recent advances in unraveling the ongoing battle.
    Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.
      Glutamine metabolism plays a pivotal role in cancer progression, immune cell function, and the modulation of the tumor microenvironment. Dysregulated glutamine metabolism has been implicated in cancer development and immune responses, supported by mounting evidence. Cancer cells heavily rely on glutamine as a critical nutrient for survival and proliferation, while immune cells require glutamine for activation and proliferation during immune reactions. This metabolic competition creates a dynamic tug-of-war between cancer and immune cells. Targeting glutamine transporters and downstream enzymes involved in glutamine metabolism holds significant promise in enhancing anti-tumor immunity. A comprehensive understanding of the intricate molecular mechanisms underlying this interplay is crucial for developing innovative therapeutic approaches that improve anti-tumor immunity and patient outcomes. In this review, we provide a comprehensive overview of recent advances in unraveling the tug-of-war of glutamine metabolism between cancer and immune cells and explore potential applications of basic science discoveries in the clinical setting. Further investigations into the regulation of glutamine metabolism in cancer and immune cells are expected to yield valuable insights, paving the way for future therapeutic interventions.
    Keywords:  Cancer; Glutamine metabolism; Immune cells; Therapeutic strategies; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-024-02994-0
  22. J Immunother Cancer. 2024 Mar 07. pii: e008431. [Epub ahead of print]12(3):
    An oncolytic vaccinia virus encoding hyaluronidase reshapes the extracellular matrix to enhance cancer chemotherapy and immunotherapy.
    Shibing Wang, Yuxin Li, Chuning Xu, Jie Dong, Jiwu Wei.
       BACKGROUND: The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies.
    METHODS: We constructed a recombinant oncolytic vaccinia virus encoding the hyaluronidase, and investigated its function in remodeling the ECM of the TME, the antitumor efficacy both in vitro and in several murine solid tumors either alone, or in combination with chemo drugs including doxorubicin and gemcitabine, with polypeptide liraglutide, with immune therapeutics such as PD-L1/PD-1 blockade, CD47 antibody, and with CAR-T cells.
    RESULTS: Compared with control OVV, intratumoral injection of OVV-Hyal1 showed superior antitumor efficacies in a series of mouse subcutaneous tumor models. Moreover, HA degradation by OVV-Hyal1 resulted in increased intratumoral dissemination of chemo drugs, infiltration of T cells, NK cells, macrophages, and activation of CD8+ T cells. When OVV-Hyal1 was combined with some antitumor therapeutics, for example, doxorubicin, gemcitabine, liraglutide, anti-PD-1, anti-CD47 blockade, or CAR-T cells, more profound therapeutic outcomes were obtained.
    CONCLUSIONS: OVV-Hyal1 effectively degrades HA to reshape the TME, therefore overcoming some major hurdles in current cancer therapy, such as limited OVs spread, unfavored dissemination of chemo drugs, polypeptides, antibodies, and insufficient infiltration of effector immune cells. OVV-Hyal1 holds the promise to improve the antitumor outcomes of current cancer therapeutics.
    Keywords:  Drug Therapy, Combination; Oncolytic Virotherapy; Tumor Microenvironment
    DOI:  https://doi.org/10.1136/jitc-2023-008431
  23. Cancer Lett. 2024 Mar 05. pii: S0304-3835(24)00185-X. [Epub ahead of print] 216792
    Hypoxia effects on glioblastoma progression through YAP/TAZ pathway regulation.
    Carolina Castillo, Maddalena Grieco, Stefania D'Amone, Maria Grazia Lolli, Ornella Ursini, Barbara Cortese.
      The resistance of glioblastomas (GBM) to standard therapies poses a clinical challenge with limited survival despite interventions. The tumor microenvironment (TME) orchestrates GBM progression, comprising stromal and immune cells and is characterized by extensive hypoxic regions. Hypoxia activates the hypoxia-inducible factor 1 alpha (HIF-1α) pathway, interacting with the Hippo pathway (YAP/TAZ) in crucial cellular processes. We discuss here the related signaling crosstalk between YAP/TAZ and regions of hypoxia in the TME with particular attention on the MST1/2 and LATS1/2-regulated YAP/TAZ activation, impacting cell proliferation, invasion, and stemness. Moreover, the hypoxia-YAP/TAZ axis influence on angiogenesis, stem cells, and metabolic regulators is defined. By reviewing extracellular matrix alterations activation of YAP/TAZ, modulation of signaling pathways we also discuss the significance of spatial constraints and epigenetic modifications contribution to GBM progression, with potential therapeutic targets in YAP/TAZ-mediated gene regulation. Comprehensive understanding of the hypoxia-Hippo pathway-TME interplay offers insights for novel therapeutic strategies, aiming to provide new directions for treatment.
    Keywords:  Glioblastoma; Hippo; Hypoxia; Tumor microenvironment; YAP/TAZ
    DOI:  https://doi.org/10.1016/j.canlet.2024.216792
  24. Front Oncol. 2024 ;14 1328606
    The potential of aryl hydrocarbon receptor as receptors for metabolic changes in tumors.
    Zhiying Wang, Yuanqi Zhang, Zhihong Liao, Mingzhang Huang, Xiaorong Shui.
      Cancer cells can alter their metabolism to meet energy and molecular requirements due to unfavorable environments with oxygen and nutritional deficiencies. Therefore, metabolic reprogramming is common in a tumor microenvironment (TME). Aryl hydrocarbon receptor (AhR) is a ligand-activated nuclear transcription factor, which can be activated by many exogenous and endogenous ligands. Multiple AhR ligands can be produced by both TME and tumor cells. By attaching to various ligands, AhR regulates cancer metabolic reprogramming by dysregulating various metabolic pathways, including glycolysis, lipid metabolism, and nucleotide metabolism. These regulated pathways greatly contribute to cancer cell growth, metastasis, and evading cancer therapies; however, the underlying mechanisms remain unclear. Herein, we review the relationship between TME and metabolism and describe the important role of AhR in cancer regulation. We also focus on recent findings to discuss the idea that AhR acts as a receptor for metabolic changes in tumors, which may provide new perspectives on the direction of AhR research in tumor metabolic reprogramming and future therapeutic interventions.
    Keywords:  aryl hydrocarbon receptor; cancer; metabolic reprogramming; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2024.1328606
  25. Trends Pharmacol Sci. 2024 Mar 06. pii: S0165-6147(24)00029-4. [Epub ahead of print]
    Translational adaptation in breast cancer metastasis and emerging therapeutic opportunities.
    Siyu Chen, Albertas Navickas, Hani Goodarzi.
      Breast cancer's tendency to metastasize poses a critical barrier to effective treatment, making it a leading cause of mortality among women worldwide. A growing body of evidence is showing that translational adaptation is emerging as a key mechanism enabling cancer cells to thrive in the dynamic tumor microenvironment (TME). Here, we systematically summarize how breast cancer cells utilize translational adaptation to drive metastasis, highlighting the intricate regulation by specific translation machinery and mRNA attributes such as sequences and structures, along with the involvement of tRNAs and other trans-acting RNAs. We provide an overview of the latest findings and emerging concepts in this area, discussing their potential implications for therapeutic strategies in breast cancer.
    Keywords:  breast cancer; metastasis; stress; therapy; translational adaptation; translational reprogramming
    DOI:  https://doi.org/10.1016/j.tips.2024.02.002
  26. Cell Mol Immunol. 2024 Mar 08.
    Neutrophils in the tumor microenvironment - when a company becomes a crowd.
    Zvi G Fridlender, Zvi Granot.
      
    DOI:  https://doi.org/10.1038/s41423-024-01147-9
  27. Cell Mol Immunol. 2024 Mar 06.
    Engagement of sialylated glycans with Siglec receptors on suppressive myeloid cells inhibits anticancer immunity via CCL2.
    Ronja Wieboldt, Michael Sandholzer, Emanuele Carlini, Chia-Wei Lin, Anastasiya Börsch, Andreas Zingg, Didier Lardinois, Petra Herzig, Leyla Don, Alfred Zippelius, Heinz Läubli, Natalia Rodrigues Mantuano.
      The overexpression of sialic acids on glycans, called hypersialylation, is a common alteration found in cancer cells. Sialylated glycans can enhance immune evasion by interacting with sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on tumor-infiltrating immune cells. Here, we investigated the effect of sialylated glycans and their interaction with Siglec receptors on myeloid-derived suppressor cells (MDSCs). We found that MDSCs derived from the blood of lung cancer patients and tumor-bearing mice strongly express inhibitory Siglec receptors and are highly sialylated. In murine cancer models of emergency myelopoiesis, Siglec-E knockout in myeloid cells resulted in prolonged survival and increased tumor infiltration of activated T cells. Targeting suppressive myeloid cells by blocking Siglec receptors or desialylation strongly reduced their suppressive potential. We further identified CCL2 as a mediator involved in T-cell suppression upon interaction between sialoglycans and Siglec receptors on MDSCs. Our results demonstrated that sialylated glycans inhibit anticancer immunity by modulating CCL2 expression.
    Keywords:  Sialic acid-binding immunoglobulin-like lectin; myeloid derived suppressor cells; sialoglycans; tumor microenvironment
    DOI:  https://doi.org/10.1038/s41423-024-01142-0
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