bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–05–12
25 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. The role of tumor-associated macrophages in tumor immune evasion.
  2. Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer.
  3. Converting "cold" to "hot": epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells.
  4. Key players of immunosuppression in epithelial malignancies: Tumor-infiltrating myeloid cells and γδ T cells.
  5. Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion.
  6. Cleanup on IL-2.
  7. Strategies to reprogram anti-inflammatory macrophages towards pro-inflammatory macrophages to support cancer immunotherapies.
  8. Fructose-induced metabolic reprogramming of cancer cells.
  9. Havoc in harmony: Unravelling the intricacies of angiogenesis orchestrated by the tumor microenvironment.
  10. Glycosylation Targeting: A Paradigm Shift in Cancer Immunotherapy.
  11. Exosomal PD-L1 in cancer and other fields: recent advances and perspectives.
  12. Signaling crosstalk between tumor endothelial cells and immune cells in the microenvironment of solid tumors.
  13. Development of 42 marker panel for in-depth study of cancer associated fibroblast niches in breast cancer using imaging mass cytometry.
  14. Function of alveolar macrophages in lung cancer microenvironment.
  15. Epigenetic Modulations in Triple-Negative Breast Cancer: Therapeutic Implications for Tumor Microenvironment.
  16. Targeting tumorous Circ-E-Cadherinencoded C-E-Cad inhibits the recruitment and function of breast cancer-associated myeloid-derived suppressor cells.
  17. [Research progress on ferroptosis in tumor immunity].
  18. An emerging strategy: probiotics enhance the effectiveness of tumor immunotherapy via mediating the gut microbiome.
  19. Evolving Tumor Characteristics and Smart Nanodrugs for Tumor Immunotherapy.
  20. State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future?
  21. Targeting PD-L1 in solid cancer with myeloid cells expressing a CAR-like immune receptor.
  22. Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.
  23. Autophagy in glioblastoma: A mechanistic perspective.
  24. Stromal B Lymphocytes Affecting Prognosis in Triple-Negative Breast Cancer by Opal/TSA Multiplexed Immunofluorescence.
  25. Hydroxygenkwanin Suppresses Peritoneal Metastasis in Colorectal Cancer by Modulating Tumor-associated Macrophages Polarization.
  1. J Cancer Res Clin Oncol. 2024 May 07. 150(5): 238
    The role of tumor-associated macrophages in tumor immune evasion.
    Ruizhe Huang, Ting Kang, Siyu Chen.
       BACKGROUND: Tumor growth is closely linked to the activities of various cells in the tumor microenvironment (TME), particularly immune cells. During tumor progression, circulating monocytes and macrophages are recruited, altering the TME and accelerating growth. These macrophages adjust their functions in response to signals from tumor and stromal cells. Tumor-associated macrophages (TAMs), similar to M2 macrophages, are key regulators in the TME.
    METHODS: We review the origins, characteristics, and functions of TAMs within the TME. This analysis includes the mechanisms through which TAMs facilitate immune evasion and promote tumor metastasis. Additionally, we explore potential therapeutic strategies that target TAMs.
    RESULTS: TAMs are instrumental in mediating tumor immune evasion and malignant behaviors. They release cytokines that inhibit effector immune cells and attract additional immunosuppressive cells to the TME. TAMs primarily target effector T cells, inducing exhaustion directly, influencing activity indirectly through cellular interactions, or suppressing through immune checkpoints. Additionally, TAMs are directly involved in tumor proliferation, angiogenesis, invasion, and metastasis. Developing innovative tumor-targeted therapies and immunotherapeutic strategies is currently a promising focus in oncology. Given the pivotal role of TAMs in immune evasion, several therapeutic approaches have been devised to target them. These include leveraging epigenetics, metabolic reprogramming, and cellular engineering to repolarize TAMs, inhibiting their recruitment and activity, and using TAMs as drug delivery vehicles. Although some of these strategies remain distant from clinical application, we believe that future therapies targeting TAMs will offer significant benefits to cancer patients.
    Keywords:  Immune evasion; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00432-024-05777-4
  2. Mol Cancer. 2024 May 07. 23(1): 92
    Modulation of the tumor microenvironment and mechanism of immunotherapy-based drug resistance in breast cancer.
    Moumita Kundu, Ramesh Butti, Venketesh K Panda, Diksha Malhotra, Sumit Das, Tandrima Mitra, Prachi Kapse, Suresh W Gosavi, Gopal C Kundu.
      Breast cancer, the most frequent female malignancy, is often curable when detected at an early stage. The treatment of metastatic breast cancer is more challenging and may be unresponsive to conventional therapy. Immunotherapy is crucial for treating metastatic breast cancer, but its resistance is a major limitation. The tumor microenvironment (TME) is vital in modulating the immunotherapy response. Various tumor microenvironmental components, such as cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), are involved in TME modulation to cause immunotherapy resistance. This review highlights the role of stromal cells in modulating the breast tumor microenvironment, including the involvement of CAF-TAM interaction, alteration of tumor metabolism leading to immunotherapy failure, and other latest strategies, including high throughput genomic screening, single-cell and spatial omics techniques for identifying tumor immune genes regulating immunotherapy response. This review emphasizes the therapeutic approach to overcome breast cancer immune resistance through CAF reprogramming, modulation of TAM polarization, tumor metabolism, and genomic alterations.
    Keywords:  Breast cancer; Cancer-associated fibroblast; Immune resistance; Therapeutic approach; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1186/s12943-024-01990-4
  3. Cancer Commun (Lond). 2024 May 07.
    Converting "cold" to "hot": epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells.
    Yijia Tang, Guangzu Cui, Haicong Liu, Ying Han, Changjing Cai, Ziyang Feng, Hong Shen, Shan Zeng.
      Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called "cold" tumors which are unresponsive to immunotherapy, and the opposite are "hot" tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of "cold" tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming "cold" tumors into "hot" tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in "cold" tumor.
    Keywords:  DNA methylation; epigenetics strategy; histone modification; immune suppressive cell; non‐coding RNA
    DOI:  https://doi.org/10.1002/cac2.12546
  4. Cancer Rep (Hoboken). 2024 May;7(5): e2066
    Key players of immunosuppression in epithelial malignancies: Tumor-infiltrating myeloid cells and γδ T cells.
    Baishali Tamuli, Sakshi Sharma, Meena Patkar, Subir Biswas.
       BACKGROUND: The tumor microenvironment of solid tumors governs the differentiation of otherwise non-immunosuppressive macrophages and gamma delta (γδ) T cells into strong immunosuppressors while promoting suppressive abilities of known immunosuppressors such as myeloid-derived suppressor cells (MDSCs) upon infiltration into the tumor beds.
    RECENT FINDINGS: In epithelial malignancies, tumor-associated macrophages (TAMs), precursor monocytic MDSCs (M-MDSCs), and gamma delta (γδ) T cells often acquire strong immunosuppressive abilities that dampen spontaneous immune responses by tumor-infiltrating T cells and B lymphocytes against cancer. Both M-MDSCs and γδ T cells have been associated with worse prognosis for multiple epithelial cancers.
    CONCLUSION: Here we discuss recent discoveries on how tumor-associated macrophages and precursor M-MDSCs as well as tumor associated-γδ T cells acquire immunosuppressive abilities in the tumor beds, promote cancer metastasis, and perspectives on how possible novel interventions could restore the effective adaptive immune responses in epithelial cancers.
    Keywords:  MDSCs; gamma delta T cells; immunology; immunotherapy; tumor microenvironment; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/cnr2.2066
  5. Cell Commun Signal. 2024 May 07. 22(1): 259
    Deubiquitinating enzymes: potential regulators of the tumor microenvironment and implications for immune evasion.
    Sheng-Kai Hsu, Chon-Kit Chou, I-Ling Lin, Wen-Tsan Chang, I-Ying Kuo, Chien-Chih Chiu.
      Ubiquitination and deubiquitination are important forms of posttranslational modification that govern protein homeostasis. Deubiquitinating enzymes (DUBs), a protein superfamily consisting of more than 100 members, deconjugate ubiquitin chains from client proteins to regulate cellular homeostasis. However, the dysregulation of DUBs is reportedly associated with several diseases, including cancer. The tumor microenvironment (TME) is a highly complex entity comprising diverse noncancerous cells (e.g., immune cells and stromal cells) and the extracellular matrix (ECM). Since TME heterogeneity is closely related to tumorigenesis and immune evasion, targeting TME components has recently been considered an attractive therapeutic strategy for restoring antitumor immunity. Emerging studies have revealed the involvement of DUBs in immune modulation within the TME, including the regulation of immune checkpoints and immunocyte infiltration and function, which renders DUBs promising for potent cancer immunotherapy. Nevertheless, the roles of DUBs in the crosstalk between tumors and their surrounding components have not been comprehensively reviewed. In this review, we discuss the involvement of DUBs in the dynamic interplay between tumors, immune cells, and stromal cells and illustrate how dysregulated DUBs facilitate immune evasion and promote tumor progression. We also summarize potential small molecules that target DUBs to alleviate immunosuppression and suppress tumorigenesis. Finally, we discuss the prospects and challenges regarding the targeting of DUBs in cancer immunotherapeutics and several urgent problems that warrant further investigation.
    Keywords:  Cytotoxic T cell (CTL); Deubiquitinating enzymes (DUBs); Immune evasion; Posttranslational modification (PTM); Regulatory T cell (Treg); Tumor microenvironment (TME); Tumor-associated macrophage (TAM)
    DOI:  https://doi.org/10.1186/s12964-024-01633-7
  6. Sci Signal. 2024 May 07. 17(835): eadq1964
    Cleanup on IL-2.
    Amy E Baek.
      Prostaglandins in the tumor microenvironment block IL-2-induced expansion of killer T cells.
    DOI:  https://doi.org/10.1126/scisignal.adq1964
  7. Immunol Lett. 2024 May 03. pii: S0165-2478(24)00038-5. [Epub ahead of print]267 106864
    Strategies to reprogram anti-inflammatory macrophages towards pro-inflammatory macrophages to support cancer immunotherapies.
    Ana Vizcaino Castro, Toos Daemen, Cesar Oyarce.
      Tumor-associated myeloid cells, including macrophages and myeloid-derived suppressor cells, can be highly prevalent in solid tumors and play a significant role in the development of the tumor. Therefore, myeloid cells are being considered potential targets for cancer immunotherapies. In this review, we focused on strategies aimed at targeting tumor-associated macrophages (TAMs). Most strategies were studied preclinically but we also included a limited number of clinical studies based on these strategies. We describe possible underlying mechanisms and discuss future challenges and prospects.
    Keywords:  Cancer immunotherapies; Polarization; Reprogramming; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.imlet.2024.106864
  8. Front Immunol. 2024 ;15 1375461
    Fructose-induced metabolic reprogramming of cancer cells.
    Kenneth K Y Ting.
      Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.
    Keywords:  GLUT5; cancer; fructose; glycolysis; ketohexokinase (KHK); metabolic reprogramming; metabolism; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fimmu.2024.1375461
  9. Cancer Treat Rev. 2024 May 01. pii: S0305-7372(24)00077-X. [Epub ahead of print]127 102749
    Havoc in harmony: Unravelling the intricacies of angiogenesis orchestrated by the tumor microenvironment.
    Sushree Subhadra Acharya, Chanakya Nath Kundu.
      Cancer cells merely exist in isolation; rather, they exist in an intricate microenvironment composed of blood vessels, signalling molecules, immune cells, stroma, fibroblasts, and the ECM. The TME provides a setting that is favourable for the successful growth and survivance of tumors. Angiogenesis is a multifaceted process that is essential for the growth, invasion, and metastasis of tumors. TME can be visualized as a "concert hall," where various cellular and non-cellular factors perform in a "symphony" to orchestrate tumor angiogenesis and create "Havoc" instead of "Harmony". In this review, we comprehensively summarized the involvement of TME in regulating tumor angiogenesis. Especially, we have focused on immune cells and their secreted factors, inflammatory cytokines and chemokines, and their role in altering the TME. We have also deciphered the crosstalk among various cell types that further aids the process of tumor angiogenesis. Additionally, we have highlighted the limitations of existing anti-angiogenic therapy and discussed various potential strategies that could be used to overcome these challenges and improve the efficacy of anti-angiogenic therapy.
    Keywords:  Cytokines; Immune cells; Oncoimmunology; Tumor angiogenesis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ctrv.2024.102749
  10. Int J Biol Sci. 2024 ;20(7): 2607-2621
    Glycosylation Targeting: A Paradigm Shift in Cancer Immunotherapy.
    Xueting Ren, Shuai Lin, Feng Guan, Huafeng Kang.
      Immunotherapy has shown great potential in cancer treatment. However, even with the intervention of techniques such as immune checkpoint inhibitor therapy, tumors can still achieve immune escape, leading to a low response rate. Abnormal glycosylation is a widely recognized hallmark of cancer. The development of a complex "glyco-code" on the surface of tumor cells can potentially influence the immune system's ability to monitor tumors and can impact the anti-tumor immune response. Therefore, abnormal glycosylation has emerged as a promising target for immunotherapy. Many recent studies have shown that targeted glycosylation can reshape the tumor microenvironment (TME) and promote the immune response, thereby improving the response to immunotherapy. This review summarizes how glycosylation affects anti-tumor immune function in the TME and synthesizes the latest research progress on targeted glycosylation in immunotherapy. It is hoped that by elucidating the basic laws and biological connotations of glycosylation, this review will enable researcher to thoroughly analyze the mechanism of its influence on the immune metabolic regulation network, which will provide a theoretical tool for promoting the clinical application of glycosylation codes.
    DOI:  https://doi.org/10.7150/ijbs.93806
  11. Front Immunol. 2024 ;15 1395332
    Exosomal PD-L1 in cancer and other fields: recent advances and perspectives.
    Man-Man Lu, Yu Yang.
      PD-1/PD-L1 signaling is a key factor of local immunosuppression in the tumor microenvironment. Immune checkpoint inhibitors targeting PD-1/PD-L1 signaling have achieved tremendous success in clinic. However, several types of cancer are particularly refractory to the anti-PD-1/PD-L1 treatment. Recently, a series of studies reported that IFN-γ can stimulate cancer cells to release exosomal PD-L1 (exoPD-L1), which possesses the ability to suppress anticancer immune responses and is associated with anti-PD-1 response. In this review, we introduce the PD-1/PD-L1 signaling, including the so-called 'reverse signaling'. Furthermore, we summarize the immune treatments of cancers and pay more attention to immune checkpoint inhibitors targeting PD-1/PD-L1 signaling. Additionally, we review the action mechanisms and regulation of exoPD-L1. We also introduce the function of exoPD-L1 as biomarkers. Finally, we review the methods for analyzing and quantifying exoPD-L1, the therapeutic strategies targeting exoPD-L1 to enhance immunotherapy and the roles of exoPD-L1 beyond cancer. This comprehensive review delves into recent advances of exoPD-L1 and all these findings suggest that exoPD-L1 plays an important role in both cancer and other fields.
    Keywords:  PD-L1; biomarker; exosomal PD-L1; exosome; immune checkpoint; immunotherapy; resistance
    DOI:  https://doi.org/10.3389/fimmu.2024.1395332
  12. Front Cell Dev Biol. 2024 ;12 1387198
    Signaling crosstalk between tumor endothelial cells and immune cells in the microenvironment of solid tumors.
    Yuexin Xu, Chris P Miller, Scott S Tykodi, Shreeram Akilesh, Edus H Warren.
      Tumor-associated endothelial cells (TECs) are crucial mediators of immune surveillance and immune escape in the tumor microenvironment (TME). TECs driven by angiogenic growth factors form an abnormal vasculature which deploys molecular machinery to selectively promote the function and recruitment of immunosuppressive cells while simultaneously blocking the entry and function of anti-tumor immune cells. TECs also utilize a similar set of signaling regulators to promote the metastasis of tumor cells. Meanwhile, the tumor-infiltrating immune cells further induce the TEC anergy by secreting pro-angiogenic factors and prevents further immune cell penetration into the TME. Understanding the complex interactions between TECs and immune cells will be needed to successfully treat cancer patients with combined therapy to achieve vasculature normalization while augmenting antitumor immunity. In this review, we will discuss what is known about the signaling crosstalk between TECs and tumor-infiltrating immune cells to reveal insights and strategies for therapeutic targeting.
    Keywords:  angiogenesis; immune cell transmigration; immune suppression; tumor endothelial cell; tumor microenvironment across the tumor endothelium
    DOI:  https://doi.org/10.3389/fcell.2024.1387198
  13. Front Immunol. 2024 ;15 1325191
    Development of 42 marker panel for in-depth study of cancer associated fibroblast niches in breast cancer using imaging mass cytometry.
    Hanna Røgenes, Kenneth Finne, Ingeborg Winge, Lars A Akslen, Arne Östman, Vladan Milosevic.
      Imaging Mass Cytometry (IMC) is a novel, and formidable high multiplexing imaging method emerging as a promising tool for in-depth studying of tissue architecture and intercellular communications. Several studies have reported various IMC antibody panels mainly focused on studying the immunological landscape of the tumor microenvironment (TME). With this paper, we wanted to address cancer associated fibroblasts (CAFs), a component of the TME very often underrepresented and not emphasized enough in present IMC studies. Therefore, we focused on the development of a comprehensive IMC panel that can be used for a thorough description of the CAF composition of breast cancer TME and for an in-depth study of different CAF niches in relation to both immune and breast cancer cell communication. We established and validated a 42 marker panel using a variety of control tissues and rigorous quantification methods. The final panel contained 6 CAF-associated markers (aSMA, FAP, PDGFRa, PDGFRb, YAP1, pSMAD2). Breast cancer tissues (4 cases of luminal, 5 cases of triple negative breast cancer) and a modified CELESTA pipeline were used to demonstrate the utility of our IMC panel for detailed profiling of different CAF, immune and cancer cell phenotypes.
    Keywords:  breast cancer; cancer associated fibroblasts; imaging mass cytometry; microniches; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1325191
  14. Inflamm Regen. 2024 May 08. 44(1): 23
    Function of alveolar macrophages in lung cancer microenvironment.
    Takahiro Matsui, Seiji Taniguchi, Masaru Ishii.
       BACKGROUND: Cancer tissues contain a wide variety of immune cells that play critical roles in suppressing or promoting tumor progression. Macrophages are one of the most predominant populations in the tumor microenvironment and are composed of two classes: infiltrating macrophages from the bone marrow and tissue-resident macrophages (TRMs). This review aimed to outline the function of TRMs in the tumor microenvironment, focusing on lung cancer.
    REVIEW: Although the functions of infiltrating macrophages and tumor-associated macrophages have been intensively analyzed, a comprehensive understanding of TRM function in cancer is relatively insufficient because it differs depending on the tissue and organ. Alveolar macrophages (AMs), one of the most important TRMs in the lungs, are replenished in situ, independent of hematopoietic stem cells in the bone marrow, and are abundant in lung cancer tissue. Recently, we reported that AMs support cancer cell proliferation and contribute to unfavorable outcomes.
    CONCLUSION: In this review, we introduce the functions of AMs in lung cancer and their underlying molecular mechanisms. A thorough understanding of the functions of AMs in lung cancer will lead to improved treatment outcomes.
    Keywords:   INHBA ; Activin A; Alveolar macrophage; Cancer microenvironment; Lung cancer; Tissue-resident macrophage
    DOI:  https://doi.org/10.1186/s41232-024-00335-4
  15. Pharmacol Res. 2024 May 06. pii: S1043-6618(24)00149-X. [Epub ahead of print] 107205
    Epigenetic Modulations in Triple-Negative Breast Cancer: Therapeutic Implications for Tumor Microenvironment.
    Linlin Zhou, Chen-Wei Yu.
      Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptors, progesterone receptors and lacks HER2 overexpression. This absence of critical molecular targets poses significant challenges for conventional therapies. Immunotherapy, remarkably immune checkpoint blockade, offers promise for TNBC treatment, but its efficacy remains limited. Epigenetic dysregulation, including altered DNA methylation, histone modifications, and imbalances in regulators such as BET proteins, plays a crucial role in TNBC development and resistance to treatment. Hypermethylation of tumor suppressor gene promoters and the imbalance of histone methyltransferases such as EZH2 and histone deacetylases (HDACs) profoundly influence tumor cell proliferation, survival, and metastasis. In addition, epigenetic alterations critically shape the tumor microenvironment (TME), including immune cell composition, cytokine signaling, and immune checkpoint expression, ultimately contributing to immune evasion. Targeting these epigenetic mechanisms with specific inhibitors such as EZH2 and HDAC inhibitors in combination with immunotherapy represents a compelling strategy to remodel the TME, potentially overcoming immune evasion and enhancing therapeutic outcomes in TNBC. This review aims to comprehensively elucidate the current understanding of epigenetic modulation in TNBC, its influence on the TME, and the potential of combining epigenetic therapies with immunotherapy to overcome the challenges posed by this aggressive breast cancer subtype.
    Keywords:  Triple-negative breast cancer; epigenetic modulation and combination; immunotherapy
    DOI:  https://doi.org/10.1016/j.phrs.2024.107205
  16. Pharmacol Res. 2024 May 02. pii: S1043-6618(24)00148-8. [Epub ahead of print] 107204
    Targeting tumorous Circ-E-Cadherinencoded C-E-Cad inhibits the recruitment and function of breast cancer-associated myeloid-derived suppressor cells.
    Junyi Zhou, Hao Xu, Xixi Li, Huantao Liu, Zicheng Sun, Jie Li, Yiyu Tang, Huali Gao, Kun Zhao, Changyuan Ding, Xinya Gao.
      We previously demonstrated that the C-E-cad protein encoded by circ-E-cadherin promotes the self-renewal of glioma stem cells. The expression pattern of C-E-cad in breast cancer and its potential function in the tumor microenvironment are unclear. The expression of circ-E-cadherin and C-E-cad was detected in breast cancer specimens. The influence of C-E-cad expression on MDSCs was assessed using FACS and in vivo tumorigenesis experiments. The synergistic effect of anti-C-E-cad and anti-PD-1 antibodies was validated in vivo. circ-E-cadherin and the encoded protein C-E-cad were found to be upregulated in breast cancer vs. normal samples. C-E-cad promotes the recruitment of MDSCs, especially PMN-MDSCs. C-E-cad activates EGFR signaling in tumor cells and promotes the transcription of CXCL8; moreover, C-E-cad binds to MDSCs and maintains glycolysis in PMN-MDSCs. Targeting C-E-cad enhanced anti-PD-1 efficiency. Our data suggested that C-E-cad is markedly overexpressed in breast cancer and promotes MDSC recruitment and survival. Targeting C-E-cad increases the efficacy of immune checkpoint inhibitor therapy.
    Keywords:  ICI; MDSC; breast cancer; circRNA
    DOI:  https://doi.org/10.1016/j.phrs.2024.107204
  17. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Apr;40(4): 362-366
    [Research progress on ferroptosis in tumor immunity].
    Jianghong Ji, Sai Liu, Xiang Liao, Dongqing Wang, Haitao Zhu.
      Ferroptosis is a novel form of cell death that is induced by excessive accumulation of ferrous ions and lipid peroxides. It triggers the release of damage-associated molecular patterns through autophagy-dependent mechanisms, serving as an adjunct to immunogenic cell death and activating both adaptive and innate immunity. In the tumor microenvironment, the regulation and influence of tumor cells and immune cells undergoing ferroptosis are regulated by various factors, which plays a crucial role in tumor development, treatment, and prognosis. This article provides an overview of the biological effects of ferroptosis on immune cells such as T cells, macrophages, neutrophils and B cells and tumor cells in the tumor microenvironment.
  18. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2341717
    An emerging strategy: probiotics enhance the effectiveness of tumor immunotherapy via mediating the gut microbiome.
    Shuaiming Jiang, Wenyao Ma, Chenchen Ma, Zeng Zhang, Wanli Zhang, Jiachao Zhang.
      The occurrence and progression of tumors are often accompanied by disruptions in the gut microbiota. Inversely, the impact of the gut microbiota on the initiation and progression of cancer is becoming increasingly evident, influencing the tumor microenvironment (TME) for both local and distant tumors. Moreover, it is even suggested to play a significant role in the process of tumor immunotherapy, contributing to high specificity in therapeutic outcomes and long-term effectiveness across various cancer types. Probiotics, with their generally positive influence on the gut microbiota, may serve as effective agents in synergizing cancer immunotherapy. They play a crucial role in activating the immune system to inhibit tumor growth. In summary, this comprehensive review aims to provide valuable insights into the dynamic interactions between probiotics, gut microbiota, and cancer. Furthermore, we highlight recent advances and mechanisms in using probiotics to improve the effectiveness of cancer immunotherapy. By understanding these complex relationships, we may unlock innovative approaches for cancer diagnosis and treatment while optimizing the effects of immunotherapy.
    Keywords:  Probiotics; gut microbiome; tumor immunotherapy; tumor microbiome; tumor microenvironment
    DOI:  https://doi.org/10.1080/19490976.2024.2341717
  19. Int J Nanomedicine. 2024 ;19 3919-3942
    Evolving Tumor Characteristics and Smart Nanodrugs for Tumor Immunotherapy.
    Wenshe Sun, Shaowei Xie, Shi Feng Liu, Xiaokun Hu, Dongming Xing.
      Typical physiological characteristics of tumors, such as weak acidity, low oxygen content, and upregulation of certain enzymes in the tumor microenvironment (TME), provide survival advantages when exposed to targeted attacks by drugs and responsive nanomedicines. Consequently, cancer treatment has significantly progressed in recent years. However, the evolution and adaptation of tumor characteristics still pose many challenges for current treatment methods. Therefore, efficient and precise cancer treatments require an understanding of the heterogeneity degree of various factors in cancer cells during tumor evolution to exploit the typical TME characteristics and manage the mutation process. The highly heterogeneous tumor and infiltrating stromal cells, immune cells, and extracellular components collectively form a unique TME, which plays a crucial role in tumor malignancy, including proliferation, invasion, metastasis, and immune escape. Therefore, the development of new treatment methods that can adapt to the evolutionary characteristics of tumors has become an intense focus in current cancer treatment research. This paper explores the latest understanding of cancer evolution, focusing on how tumors use new antigens to shape their "new faces"; how immune system cells, such as cytotoxic T cells, regulatory T cells, macrophages, and natural killer cells, help tumors become "invisible", that is, immune escape; whether the diverse cancer-associated fibroblasts provide support and coordination for tumors; and whether it is possible to attack tumors in reverse. This paper discusses the limitations of targeted therapy driven by tumor evolution factors and explores future strategies and the potential of intelligent nanomedicines, including the systematic coordination of tumor evolution factors and adaptive methods, to meet this therapeutic challenge.
    Keywords:  fibroblasts; immune cells; smart nanomedicine; tumor evolution
    DOI:  https://doi.org/10.2147/IJN.S453265
  20. Cells. 2024 Apr 23. pii: 725. [Epub ahead of print]13(9):
    State of the Art in CAR-T Cell Therapy for Solid Tumors: Is There a Sweeter Future?
    Beatriz Amorós-Pérez, Benigno Rivas-Pardo, Manuel Gómez Del Moral, José Luis Subiza, Eduardo Martínez-Naves.
      Chimeric antigen receptor (CAR)-T cell therapy has proven to be a powerful treatment for hematological malignancies. The situation is very different in the case of solid tumors, for which no CAR-T-based therapy has yet been approved. There are many factors contributing to the absence of response in solid tumors to CAR-T cells, such as the immunosuppressive tumor microenvironment (TME), T cell exhaustion, or the lack of suitable antigen targets, which should have a stable and specific expression on tumor cells. Strategies being developed to improve CAR-T-based therapy for solid tumors include the use of new-generation CARs such as TRUCKs or bi-specific CARs, the combination of CAR therapy with chemo- or radiotherapy, the use of checkpoint inhibitors, and the use of oncolytic viruses. Furthermore, despite the scarcity of targets, a growing number of phase I/II clinical trials are exploring new solid-tumor-associated antigens. Most of these antigens are of a protein nature; however, there is a clear potential in identifying carbohydrate-type antigens associated with tumors, or carbohydrate and proteoglycan antigens that emerge because of aberrant glycosylations occurring in the context of tumor transformation.
    Keywords:  CAR-T cells; cancer; chimeric antigen receptors; immunotherapy; solid tumors
    DOI:  https://doi.org/10.3390/cells13090725
  21. Front Immunol. 2024 ;15 1380065
    Targeting PD-L1 in solid cancer with myeloid cells expressing a CAR-like immune receptor.
    Kayla Myers Chen, Daniel Grun, Brian Gautier, Shivaprasad Venkatesha, Michael Maddox, Ai-Hong Zhang, Peter Andersen.
       Introduction: Solid cancers Myeloid cells are prevalent in solid cancers, but they frequently exhibit an anti-inflammatory pro-tumor phenotype that contribute to the immunosuppressive tumor microenvironment (TME), which hinders the effectiveness of cancer immunotherapies. Myeloid cells' natural ability of tumor trafficking makes engineered myeloid cell therapy an intriguing approach to tackle the challenges posed by solid cancers, including tumor infiltration, tumor cell heterogenicity and the immunosuppressive TME. One such engineering approach is to target the checkpoint molecule PD-L1, which is often upregulated by solid cancers to evade immune responses.
    Method: Here we devised an adoptive cell therapy strategy based on myeloid cells expressing a Chimeric Antigen Receptor (CAR)-like immune receptor (CARIR). The extracellular domain of CARIR is derived from the natural inhibitory receptor PD-1, while the intracellular domain(s) are derived from CD40 and/or CD3ζ. To assess the efficacy of CARIR-engineered myeloid cells, we conducted proof-of-principle experiments using co-culture and flow cytometry-based phagocytosis assays in vitro. Additionally, we employed a fully immune-competent syngeneic tumor mouse model to evaluate the strategy's effectiveness in vivo.
    Result: Co-culturing CARIR-expressing human monocytic THP-1 cells with PD-L1 expressing target cells lead to upregulation of the costimulatory molecule CD86 along with expression of proinflammatory cytokines TNF-1α and IL-1β. Moreover, CARIR expression significantly enhanced phagocytosis of multiple PD-L1 expressing cancer cell lines in vitro. Similar outcomes were observed with CARIR-expressing human primary macrophages. In experiments conducted in syngeneic BALB/c mice bearing 4T1 mammary tumors, infusing murine myeloid cells that express a murine version of CARIR significantly slowed tumor growth and prolonged survival.
    Conclusion: Taken together, these results demonstrate that adoptive transfer of PD-1 CARIR-engineered myeloid cells represents a promising strategy for treating PD-L1 positive solid cancers.
    Keywords:  PD-1; PD-L1; adoptive cell therapy; chimeric antigen receptor (CAR); macrophages; phagocytosis; solid cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1380065
  22. Int J Biol Sci. 2024 ;20(7): 2779-2789
    Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.
    Rui Liang, Aoyu Cheng, Shengxin Lu, Xiaokun Zhang, Maomao Ren, Jiayi Lin, Ye Wu, Weidong Zhang, Xin Luan.
      Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field.
    Keywords:  Cancer; Immunotherapy; Metabolic reprogramming; Selenium; Seleno-amino acid
    DOI:  https://doi.org/10.7150/ijbs.95484
  23. Int J Cancer. 2024 May 08.
    Autophagy in glioblastoma: A mechanistic perspective.
    Durgesh Meena, Sushmita Jha.
      Glioblastoma (GBM) is one of the most lethal malignancies in humans. Even after surgical resection and aggressive radio- or chemotherapies, patients with GBM can survive for less than 14 months. Extreme inter-tumor and intra-tumor heterogeneity of GBM poses a challenge for resolving recalcitrant GBM pathophysiology. GBM tumor microenvironment (TME) exhibits diverse heterogeneity in cellular composition and processes contributing to tumor progression and therapeutic resistance. Autophagy is such a cellular process; that demonstrates a cell-specific and TME context-dependent role in GBM progression, leading to either the promotion or suppression of GBM progression. Autophagy can regulate GBM cell function directly via regulation of survival, migration, and invasion, or indirectly by affecting GBM TME composition such as immune cell population, tumor metabolism, and glioma stem cells. This review comprehensively investigates the role of autophagy in GBM pathophysiology.
    Keywords:  autophagy; glioblastoma; glioma stem cells; innate immunity; tumor metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1002/ijc.34991
  24. Int J Womens Health. 2024 ;16 755-767
    Stromal B Lymphocytes Affecting Prognosis in Triple-Negative Breast Cancer by Opal/TSA Multiplexed Immunofluorescence.
    Min Fang, Wei Yin, Chunyan Qiu, Tao Song, Baihua Lin, Ying Wang, Hanchu Xiong, Shixiu Wu.
       Objective: Immune cells play a key role in tumor microenvironment. The purpose of this study was to investigate the infiltration and clinical indication of immune cells including their combined prognostic value in microenvironment of triple negative breast cancer.
    Methods: We investigated 100 patients with triple negative breast cancer by Opal/Tyramide Signal Amplification multispectral immunofluorescence between 2003 and 2017 at Zhejiang Provincial people's Hospital. Intratumoral and stromal immune cells of triple negative breast cancer were classified and quantitatively analyzed. Survival outcomes were compared using the Kaplan-Meier method and further analyzed with multivariate analysis.
    Results: Infiltration level of stromal B lymphocytes, stromal and intratumoral CD8+ T cells, stromal CD4+ T cells, stromal PD-L1 and intratumoral tumor associated macrophages 2 cells were shown as independent factors affecting disease-free survival and overall survival in univariate analysis. Stromal B lymphocytes, T stage, N stage and pathological type were independent predictive factors for both DFS and OS in multivariate analysis. We firstly found that patients with B lymphocytes-enriched subtypes have a better prognosis than those with T lymphocytes-enriched subtypes and tumor-associated macrophage-enriched subtypes.
    Conclusion: The present study identified a bunch of immune targets and subtypes, which could be exploited in future combined immunotherapy/chemotherapy strategies for triple negative breast cancer patients.
    Keywords:  B lymphocytes; T lymphocytes; multispectral immunofluorescence; prognosis; triple negative breast cancer; tumor associated macrophages
    DOI:  https://doi.org/10.2147/IJWH.S444202
  25. Chem Biol Interact. 2024 May 06. pii: S0009-2797(24)00184-4. [Epub ahead of print] 111038
    Hydroxygenkwanin Suppresses Peritoneal Metastasis in Colorectal Cancer by Modulating Tumor-associated Macrophages Polarization.
    Jing Xun, Zhibo Hu, Meilin Wang, Xiaolin Jiang, Bin Liu, Yingdi Han, Ruifang Gao, Xueliang Wu, Aimin Zhang, Shimin Yang, Ximo Wang, Xiangyang Yu, Qi Zhang.
      Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p-NF-κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.
    Keywords:  Colorectal cancer; Hydroxygenkwanin; Macrophage polarization; Peritoneal metastasis; Tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.1016/j.cbi.2024.111038
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