bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–01–21
27 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
  2. Nano-enhanced immunotherapy: Targeting the immunosuppressive tumor microenvironment.
  3. Tissue biomarkers of immune checkpoint inhibitor therapy.
  4. Role of the tumor microenvironment in CLL pathogenesis.
  5. Evaluation of regulatory T-cells in cancer immunotherapy: therapeutic relevance of immune checkpoint inhibition.
  6. Tumor-associated macrophages in colorectal cancer metastasis: molecular insights and translational perspectives.
  7. Targeting tumor-associated macrophages: Novel insights into immunotherapy of skin cancer.
  8. The impact of tumor microenvironment: unraveling the role of physical cues in breast cancer progression.
  9. Role of autophagy in cancer-associated fibroblast activation, signaling and metabolic reprograming.
  10. Breast cancer cells and adipocytes in hypoxia: metabolism regulation.
  11. Editorial: The role of tumor microenvironment in the development, treatment and prognosis of hepatocellular carcinoma.
  12. Immune checkpoints targeting dendritic cells for antibody-based modulation in cancer.
  13. Research progress on mitochondria regulating anti-tumor immunity.
  14. cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.
  15. Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.
  16. Adipo-oncology: adipocyte-derived factors govern engraftment, survival, and progression of metastatic cancers.
  17. Alteration of functionality and differentiation directed by changing gene expression patterns in myeloid derived suppressor cells (MDSCs) in tumor microenvironment and bone marrow through early to terminal phase of tumor progression.
  18. Gel-mediated recruitment of conventional type 1 dendritic cells potentiates the therapeutic effects of radiotherapy.
  19. The crosstalk of intratumor bacteria and the tumor.
  20. Epigenetic reprogramming of T cells: unlocking new avenues for cancer immunotherapy.
  21. Role of the ubiquitin-proteasome system on macrophages in the tumor microenvironment.
  22. Wnt inhibition alleviates resistance to immune checkpoint blockade in glioblastoma.
  23. Bacteria colonization in tumor microenvironment creates a favorable niche for immunogenic chemotherapy.
  24. Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer.
  25. Understanding the Interplay of CAR-NK Cells and Triple-Negative Breast Cancer: Insights from Computational Modeling.
  26. An Adjuvant Micelle-Based Multifunctional Nanosystem for Tumor Immunotherapy by Remodeling Three Types of Immunosuppressive Cells.
  27. Intra-tumor ROS amplification by melatonin interferes in the apoptosis-autophagy-inflammation-EMT collusion in the breast tumor microenvironment.
  1. PeerJ. 2024 ;12 e16825
    Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
    Hua Cheng, Yongbin Zheng.
      Macrophages and T cells in the tumor microenvironment (TME) play an important role in tumorigenesis and progression. However, TME is also characterized by metabolic reprogramming, which may affect macrophage and metabolic activity of T cells and promote tumor escape. Immunotherapy is an approach to fight tumors by stimulating the immune system in the host, but requires support and modulation of cellular metabolism. In this process, the metabolic roles of macrophages and T cells become increasingly important, and their metabolic status and interactions play a critical role in the success of immunotherapy. Therefore, understanding the metabolic state of T cells and macrophages in the TME and the impact of metabolic reprogramming on tumor therapy will help optimize subsequent immunotherapy strategies.
    Keywords:  Immunotherapy; Macrophages; Metabolic reprogramming; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.7717/peerj.16825
  2. Biomaterials. 2024 Jan 06. pii: S0142-9612(23)00471-4. [Epub ahead of print]305 122463
    Nano-enhanced immunotherapy: Targeting the immunosuppressive tumor microenvironment.
    Yuzhi Jin, Yangyue Huang, Hui Ren, Huanhuan Huang, Chunyu Lai, Wenjun Wang, Zhou Tong, Hangyu Zhang, Wei Wu, Chuan Liu, Xuanwen Bao, Weijia Fang, Hongjun Li, Peng Zhao, Xiaomeng Dai.
      The tumor microenvironment (TME), which is mostly composed of tumor cells, immune cells, signaling molecules, stromal tissue, and the vascular system, is an integrated system that is conducive to the formation of tumors. TME heterogeneity makes the response to immunotherapy different in different tumors, such as "immune-cold" and "immune-hot" tumors. Tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells are the major suppressive immune cells and their different phenotypes interact and influence cancer cells by secreting different signaling factors, thus playing a key role in the formation of the TME as well as in the initiation, growth, and metastasis of cancer cells. Nanotechnology development has facilitated overcoming the obstacles that limit the further development of conventional immunotherapy, such as toxic side effects and lack of targeting. In this review, we focus on the role of three major suppressive immune cells in the TME as well as in tumor development, clinical trials of different drugs targeting immune cells, and different attempts to combine drugs with nanomaterials. The aim is to reveal the relationship between immunotherapy, immunosuppressive TME and nanomedicine, thus laying the foundation for further development of immunotherapy.
    Keywords:  Immunotherapy; Myeloid-derived suppressor cells; Nanomedicine; Regulatory T cells; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.biomaterials.2023.122463
  3. Immunol Cell Biol. 2024 Jan 16.
    Tissue biomarkers of immune checkpoint inhibitor therapy.
    Fatemeh Davoudi, Afshin Moradi, Habib Sadeghirad, Arutha Kulasinghe.
      Cancer immunotherapy has been rejuvenated by the growing understanding of the immune system's role in tumor activity over the past two decades. During cancer initiation and progression, tumor cells employ various mechanisms that resemble peripheral immune tolerance to evade the antitumor responses of the immune system. Immune checkpoint molecules are the major mechanism of immune resistance that are exploited by tumor cells to inhibit T-cell activation and suppress immune responses. The targeting of immune checkpoint pathways has led to substantial improvements in survival rates in a number of solid cancers. However, a lack of understanding of the heterogeneity of the tumor microenvironment (TME) has resulted in inefficient therapy responses. A greater understanding of the TME is needed to identify patients likely to respond, and those that will have resistance to immune checkpoint inhibitors (ICIs). Advancement in spatial single-cell technologies has allowed deeper insight into the phenotypic and functional diversities of cells in the TME. In this review, we provide an overview of ICI biomarkers and highlight how high-dimensional spatially resolved, single-cell approaches provide deep molecular insights into the TME and allow for the discovery of biomarkers of clinical benefit.
    Keywords:  Immune checkpoint inhibitor; single-cell RNA sequencing; spatial profiling
    DOI:  https://doi.org/10.1111/imcb.12723
  4. Semin Hematol. 2023 Dec 26. pii: S0037-1963(23)00098-7. [Epub ahead of print]
    Role of the tumor microenvironment in CLL pathogenesis.
    Alexander F Vom Stein, Michael Hallek, Phuong-Hien Nguyen.
      Chronic lymphocytic leukemia (CLL) cells extensively interact with and depend on their surrounding tumor microenvironment (TME). The TME encompasses a heterogeneous array of cell types, soluble signals, and extracellular vesicles, which contribute significantly to CLL pathogenesis. CLL cells and the TME cooperatively generate a chronic inflammatory milieu, which reciprocally reprograms the TME and activates a signaling network within CLL cells, promoting their survival and proliferation. Additionally, the inflammatory milieu exerts chemotactic effects, attracting CLL cells and other immune cells to the lymphoid tissues. The intricate CLL-TME interactions also facilitate immune evasion and compromise leukemic cell surveillance. We also review recent advances that have shed light on additional aspects that are substantially influenced by the CLL-TME interplay.
    Keywords:  CLL pathogenesis; Homing; Inflammation; Proliferation; Survival; Tumor microenvironment
    DOI:  https://doi.org/10.1053/j.seminhematol.2023.12.004
  5. Med Oncol. 2024 Jan 18. 41(2): 59
    Evaluation of regulatory T-cells in cancer immunotherapy: therapeutic relevance of immune checkpoint inhibition.
    Ranjeet Singh, Prateek Srivastava, Partha Pratim Manna.
      The evolution of the complex immune system is equipped to defend against perilous intruders and concurrently negatively regulate the deleterious effect of immune-mediated inflammation caused by self and nonself antigens. Regulatory T-cells (Tregs) are specialized cells that minimize immune-mediated inflammation, but in malignancies, this feature has been exploited toward cancer progression by keeping the antitumor immune response in check. The modulation of Treg cell infiltration and their induction in the TME (tumor microenvironment) alongside associated inhibitory molecules, both soluble or membranes tethered in the TME, have proven clinically beneficial in boosting the tumoricidal activity of the immune system. Moreover, Treg-associated immune checkpoints pose a greater obstruction in cancer immunotherapy. Inhibiting or blocking active immune checkpoint signaling in combination with other therapies has proven clinically beneficial. This review summarizes the ontogeny of Treg cells and their migration, stability, and function in the TME. We also elucidate the Treg-associated checkpoint moieties that impede effective antitumor activity and harness these molecules for effective and targeted immunotherapy against cancer nuisance.
    Keywords:  Checkpoint molecules; Homing receptors; Immune suppression; Immunotherapy; Regulatory T-cell; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12032-023-02289-y
  6. J Transl Med. 2024 Jan 16. 22(1): 62
    Tumor-associated macrophages in colorectal cancer metastasis: molecular insights and translational perspectives.
    Siyu Hou, Yuanchun Zhao, Jiajia Chen, Yuxin Lin, Xin Qi.
      Metastasis is the leading cause of high mortality in colorectal cancer (CRC), which is not only driven by changes occurring within the tumor cells, but is also influenced by the dynamic interaction between cancer cells and components in the tumor microenvironment (TME). Currently, the exploration of TME remodeling and its impact on CRC metastasis has attracted increasing attention owing to its potential to uncover novel therapeutic avenues. Noteworthy, emerging studies suggested that tumor-associated macrophages (TAMs) within the TME played important roles in CRC metastasis by secreting a variety of cytokines, chemokines, growth factors and proteases. Moreover, TAMs are often associated with poor prognosis and drug resistance, making them promising targets for CRC therapy. Given the prognostic and clinical value of TAMs, this review provides an updated overview on the origin, polarization and function of TAMs, and discusses the mechanisms by which TAMs promote the metastatic cascade of CRC. Potential TAM-targeting techniques for personalized theranostics of metastatic CRC are emphasized. Finally, future perspectives and challenges for translational applications of TAMs in CRC development and metastasis are proposed to help develop novel TAM-based strategies for CRC precision medicine and holistic healthcare.
    Keywords:  CRC metastasis; Macrophage; Personalized therapy; TAM; TME
    DOI:  https://doi.org/10.1186/s12967-024-04856-x
  7. J Adv Res. 2024 Jan 17. pii: S2090-1232(24)00026-2. [Epub ahead of print]
    Targeting tumor-associated macrophages: Novel insights into immunotherapy of skin cancer.
    Jun Liu, Jiaye Lu, Ling Wu, Tingrui Zhang, Junchao Wu, Lisha Li, Zongguang Tai, Zhongjian Chen, Quangang Zhu.
       BACKGROUND: The incidence of skin cancer is currently increasing, and conventional treatment options inadequately address the demands of disease management. Fortunately, the recent rapid advancement of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has ushered in a new era for numerous cancer patients. However, the efficacy of immunotherapy remains suboptimal due to the impact of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a major component of the TME, play crucial roles in tumor invasion, metastasis, angiogenesis, and immune evasion, significantly impacting tumor development. Consequently, TAMs have gained considerable attention in recent years, and their roles have been extensively studied in various tumors. However, the specific roles of TAMs and their regulatory mechanisms in skin cancer remain unclear.
    AIM OF REVIEW: This paper aims to elucidate the origin and classification of TAMs, investigate the interactions between TAMs and various immune cells, comprehensively understand the precise mechanisms by which TAMs contribute to the pathogenesis of different types of skin cancer, and finally discuss current strategies for targeting TAMs in the treatment of skin cancer.
    KEY SCIENTIFIC CONCEPTS OF OVERVIEW: With a specific emphasis on the interrelationship between TAMs and skin cancer, this paper posits that therapeutic modalities centered on TAMs hold promise in augmenting and harmonizing with prevailing clinical interventions for skin cancer, thereby charting a novel trajectory for advancing the landscape of immunotherapeutic approaches for skin cancer.
    Keywords:  Immune checkpoint inhibitors; Immunotherapy; Skin cancer; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.jare.2024.01.013
  8. Cancer Metastasis Rev. 2024 Jan 19.
    The impact of tumor microenvironment: unraveling the role of physical cues in breast cancer progression.
    Ayuba Akinpelu, Tosin Akinsipe, L Adriana Avila, Robert D Arnold, Panagiotis Mistriotis.
      Metastasis accounts for the vast majority of breast cancer-related fatalities. Although the contribution of genetic and epigenetic modifications to breast cancer progression has been widely acknowledged, emerging evidence underscores the pivotal role of physical stimuli in driving breast cancer metastasis. In this review, we summarize the changes in the mechanics of the breast cancer microenvironment and describe the various forces that impact migrating and circulating tumor cells throughout the metastatic process. We also discuss the mechanosensing and mechanotransducing molecules responsible for promoting the malignant phenotype in breast cancer cells. Gaining a comprehensive understanding of the mechanobiology of breast cancer carries substantial potential to propel progress in prognosis, diagnosis, and patient treatment.
    Keywords:  Breast cancer mechanobiology; Metastasis; Physical signals; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10555-024-10166-x
  9. Front Cell Dev Biol. 2023 ;11 1274682
    Role of autophagy in cancer-associated fibroblast activation, signaling and metabolic reprograming.
    Dyana Sari, Devrim Gozuacik, Yunus Akkoc.
      Tumors not only consist of cancerous cells, but they also harbor several normal-like cell types and non-cellular components. cancer-associated fibroblasts (CAFs) are one of these cellular components that are found predominantly in the tumor stroma. Autophagy is an intracellular degradation and quality control mechanism, and recent studies provided evidence that autophagy played a critical role in CAF formation, metabolic reprograming and tumor-stroma crosstalk. Therefore, shedding light on the autophagy and its role in CAF biology might help us better understand the roles of CAFs and the TME in cancer progression and may facilitate the exploitation of more efficient cancer diagnosis and treatment. Here, we provide an overview about the involvement of autophagy in CAF-related pathways, including transdifferentiation and activation of CAFs, and further discuss the implications of targeting tumor stroma as a treatment option.
    Keywords:  autophagy; cancer; cancer-associated fibroblasts (CAFs); fibroblast transdifferentiation; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fcell.2023.1274682
  10. Discov Oncol. 2024 Jan 18. 15(1): 11
    Breast cancer cells and adipocytes in hypoxia: metabolism regulation.
    Xin Yu, Tianqi Zhang, Xiaozhi Cheng, Li Ma.
      Adipocytes play a significant role in breast cancer due to the unique histological structure of the breast. These have not only been detected adjacent to breast cancer cells but they have also been implicated in cancer development. Adipocytes in obese individuals and tumor microenvironment (TME) have a common feature, that is, hypoxia. The increased expression of hypoxia-inducible factor (HIF)-1α is known to alter the metabolism and functions of adipocytes. In this study, we described the mechanism linking the hypoxia-sensing pathway manifested by HIF to adipocytes and breast cancer and discussed the mechanism underlying the role of hypoxic adipocytes in breast cancer development from the perspective of metabolic remodeling. The processes and pathways in hypoxic adipocytes could be a promising target in breast cancer therapy.
    Keywords:  Adipocytes; Breast cancer; HIF-1α; Metabolism
    DOI:  https://doi.org/10.1007/s12672-024-00865-w
  11. Front Pharmacol. 2023 ;14 1343175
    Editorial: The role of tumor microenvironment in the development, treatment and prognosis of hepatocellular carcinoma.
    Haiyu Wang, Hui Liu, Xuming Tang, Jiang Chen, Zhigang Ren.
      
    Keywords:  development; hepatocellular carcinoma; prognosis; treatment; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1343175
  12. Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(23)00120-X. [Epub ahead of print]382 145-179
    Immune checkpoints targeting dendritic cells for antibody-based modulation in cancer.
    Xin Lei, Yizhi Wang, Chayenne Broens, Jannie Borst, Yanling Xiao.
      Dendritic cells (DC) are professional antigen-presenting cells which link innate to adaptive immunity. DC play a central role in regulating antitumor T-cell responses in both tumor-draining lymph nodes (TDLN) and the tumor microenvironment (TME). They modulate effector T-cell responses via immune checkpoint proteins (ICPs) that can be either stimulatory or inhibitory. Functions of DC are often impaired by the suppressive TME leading to tumor immune escape. Therefore, better understanding of the mechanisms of action of ICPs expressed by (tumor-infiltrating) DC will lead to potential new treatment strategies. Genetic manipulation and high-dimensional analyses have provided insight in the interactions between DC and T-cells in TDLN and the TME upon ICP targeting. In this review, we discuss (tumor-infiltrating) DC lineage cells and tumor tissue specific "mature" DC states and their gene signatures in relation to anti-tumor immunity. We also review a number of ICPs expressed by DC regarding their functions in phagocytosis, DC activation, or inhibition and outline position in, or promise for clinical trials in cancer immunotherapy. Collectively, we highlight the critical role of DC and their exact status in the TME for the induction and propagation of T-cell immunity to cancer.
    DOI:  https://doi.org/10.1016/bs.ircmb.2023.07.006
  13. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Jan 05. 1-14
    Research progress on mitochondria regulating anti-tumor immunity.
    Jing Li, Pinglong Xu, Shasha Chen.
      Tumor cells adaptively reforge their metabolism to meet the demands of energy and biosynthesis. Mitochondria, pivotal organelles in the metabolic reprogramming of tumor cells, contribute to tumorigenesis and cancer progression significantly through various dysfunctions in both tumor and immune cells. Alterations in mitochondrial dynamics and metabolic signaling pathways exert crucial regulatory influence on the activation, proliferation, and differentiation of immune cells. The tumor microenvironment orchestrates the activation and functionality of tumor-infiltrating immune cells by reprogramming mitochondrial metabolism and inducing shifts in mitochondrial dynamics, thereby facilitating the establishment of a tumor immunosuppressive microenvironment. Stress-induced leakage of mitochondrial DNA contributes multifaceted regulatory effects on anti-tumor immune responses and the immunosuppressive microenvironment by activating multiple natural immune signals, including cGAS-STING, TLR9, and NLRP3. Moreover, mitochondrial DNA-mediated immunogenic cell death emerges as a promising avenue for anti-tumor immunotherapy. Additionally, mtROS, a crucial factor in tumorigenesis, drives the formation of tumor immunosuppressive microenvironment by changing the composition of immune cells within the tumor microenvironment. This review focuses on the intrinsic relationship between mitochondrial biology and anti-tumor immune responses from multiple angles. We expect to explore the core role of mitochondria in the dynamic interplay between the tumor and the host, in order to facilitate the development of targeted mitochondrial strategies for anti-tumor immunotherapy.
    Keywords:  Anti-tumor immunity; Mitochondrial DNA; Mitochondrial ROS; Mitochondrial dynamics; Mitochondrial energy metabolism; Mitochondrion; Review; Tumor microenvironment
    DOI:  https://doi.org/10.3724/zdxbyxb-2023-0484
  14. J Hematol Oncol. 2024 Jan 17. 17(1): 5
    cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.
    Hongying Zhang, Yongliang Liu, Jieya Liu, Jinzhu Chen, Jiao Wang, Hui Hua, Yangfu Jiang.
      Cancer is a complex disease resulting from abnormal cell growth that is induced by a number of genetic and environmental factors. The tumor microenvironment (TME), which involves extracellular matrix, cancer-associated fibroblasts (CAF), tumor-infiltrating immune cells and angiogenesis, plays a critical role in tumor progression. Cyclic adenosine monophosphate (cAMP) is a second messenger that has pleiotropic effects on the TME. The downstream effectors of cAMP include cAMP-dependent protein kinase (PKA), exchange protein activated by cAMP (EPAC) and ion channels. While cAMP can activate PKA or EPAC and promote cancer cell growth, it can also inhibit cell proliferation and survival in context- and cancer type-dependent manner. Tumor-associated stromal cells, such as CAF and immune cells, can release cytokines and growth factors that either stimulate or inhibit cAMP production within the TME. Recent studies have shown that targeting cAMP signaling in the TME has therapeutic benefits in cancer. Small-molecule agents that inhibit adenylate cyclase and PKA have been shown to inhibit tumor growth. In addition, cAMP-elevating agents, such as forskolin, can not only induce cancer cell death, but also directly inhibit cell proliferation in some cancer types. In this review, we summarize current understanding of cAMP signaling in cancer biology and immunology and discuss the basis for its context-dependent dual role in oncogenesis. Understanding the precise mechanisms by which cAMP and the TME interact in cancer will be critical for the development of effective therapies. Future studies aimed at investigating the cAMP-cancer axis and its regulation in the TME may provide new insights into the underlying mechanisms of tumorigenesis and lead to the development of novel therapeutic strategies.
    Keywords:  Cancer; Exchange protein activated by cAMP; Immunotherapy; PKA; Tumor microenvironment; cAMP; cAMP-dependent protein kinase
    DOI:  https://doi.org/10.1186/s13045-024-01524-x
  15. J Clin Invest. 2024 Jan 16. pii: e175445. [Epub ahead of print]134(2):
    Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer.
    Corey Dussold, Kaylee Zilinger, Jillyn Turunen, Amy B Heimberger, Jason Miska.
      Immunometabolism is a burgeoning field of research that investigates how immune cells harness nutrients to drive their growth and functions. Myeloid cells play a pivotal role in tumor biology, yet their metabolic influence on tumor growth and antitumor immune responses remains inadequately understood. This Review explores the metabolic landscape of tumor-associated macrophages, including the immunoregulatory roles of glucose, fatty acids, glutamine, and arginine, alongside the tools used to perturb their metabolism to promote antitumor immunity. The confounding role of metabolic inhibitors on our interpretation of myeloid metabolic phenotypes will also be discussed. A binary metabolic schema is currently used to describe macrophage immunological phenotypes, characterizing inflammatory M1 phenotypes, as supported by glycolysis, and immunosuppressive M2 phenotypes, as supported by oxidative phosphorylation. However, this classification likely underestimates the variety of states in vivo. Understanding these nuances will be critical when developing interventional metabolic strategies. Future research should focus on refining drug specificity and targeted delivery methods to maximize therapeutic efficacy.
    DOI:  https://doi.org/10.1172/JCI175445
  16. Cell Commun Signal. 2024 Jan 18. 22(1): 52
    Adipo-oncology: adipocyte-derived factors govern engraftment, survival, and progression of metastatic cancers.
    Shinya Sato.
      Conventional therapies for metastatic cancers have limited efficacy. Recently, cancer therapies targeting noncancerous cells in tumor microenvironments have shown improved clinical outcomes in patients. However, further advances in our understanding of the metastatic tumor microenvironment are required to improve treatment outcomes. Adipocytes are distributed throughout the body, and as a part of the metastatic tumor microenvironment, they interact with cancer cells in almost all organs. Adipocytes secrete various factors that are reported to exert clinical effects on cancer progression, including engraftment, survival, and expansion at the metastatic sites. However, only a few studies have comprehensively examined their impact on cancer cells. In this review, we examined the impact of adipocytes on cancer by describing the adipocyte-secreted factors that are involved in controlling metastatic cancer, focusing on adipokines, such as adiponectin, leptin, visfatin, chemerin, resistin, apelin, and omentin. Adipocyte-secreted factors promote cancer metastasis and contribute to various biological functions of cancer cells, including migration, invasion, proliferation, immune evasion, and drug resistance at the metastatic sites. We propose the establishment and expansion of "adipo-oncology" as a research field to enhance the comprehensive understanding of the role of adipocytes in metastatic cancers and the development of more robust metastatic cancer treatments.
    Keywords:  Adipo-oncology; Adipocyte; Adipokines; Tumor metastasis; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12964-024-01474-4
  17. J Leukoc Biol. 2024 Jan 17. pii: qiae013. [Epub ahead of print]
    Alteration of functionality and differentiation directed by changing gene expression patterns in myeloid derived suppressor cells (MDSCs) in tumor microenvironment and bone marrow through early to terminal phase of tumor progression.
    Krishna Mahanti, Jayasree Saha, Debanjan Sarkar, Anik Pramanik, Nabanita Roy Chattopadhyay, Sankar Bhattacharyya.
      Myeloid derived suppressor cells (MDSCs) are heterogenous immature myeloid lineage cells that can differentiate into neutrophils, monocytes and Dendritic cells as well (1, 2). These cells have been characterized to have potent immunosuppressive capacity in neoplasia and neoplastic chronic inflammatory microenvironment. Increased accumulation of MDSCs was reported with poor clinical outcomes in patients. They support neoplastic progression by abrogating antitumor immunity through inhibition of lymphocyte functions and directly by facilitating tumor development. Yet the shifting genetic signatures of this myeloid lineage cell towards immunosuppressive functionality in progressive tumor development remain elusive. We have attempted to identify the gene expression profile using lineage specific markers of these unique myeloid lineage cells in tumor microenvironment (TME) and bone marrow using liquid transplantable mice tumor model to trace the changing influence of TME on MDSCs. We analyzed the phenotype, functional shift, suppressive activity, differentiation status and microarray-based gene expression profile of CD11b+ Gr1+ lineage specific cells isolated from TME and bone marrow of four stages of tumor-bearing mice and compared them with control counterparts. Our analysis of differentially expressed genes of MDSCs isolated from bone marrow and TME reveals unique gene expression patterns in the bone marrow and TME-derived MDSCs. It also suggests T cell suppressive activity of MDSCs progressively increases toward mid to late phase of the tumor and a significant differentiation bias of tumor site MDSCs towards macrophage even in presence of differentiating agents indicating potential molecular characteristics of MDSCs in different stages of tumor that can emerge as intervention target.
    Keywords:  Dendritic cells; Gene expression; Immune suppression; Innate immunity; Myeloid derived suppressor cell; Neoplasia; T cell; TME
    DOI:  https://doi.org/10.1093/jleuko/qiae013
  18. Biomaterials. 2024 Jan 11. pii: S0142-9612(24)00004-8. [Epub ahead of print]305 122470
    Gel-mediated recruitment of conventional type 1 dendritic cells potentiates the therapeutic effects of radiotherapy.
    Yumin Wu, Quguang Li, Yifan Yan, Yu Hao, Chunjie Wang, Bo Liu, Yujie Zhu, Zhuang Liu, Liangzhu Feng.
      The efficacy of radiotherapy has not yet achieved optimal results, partially due to insufficient priming and infiltration of effector immune cells within the tumor microenvironment (TME), which often exhibits suppressive phenotypes. In particular, the infiltration of X-C motif chemokine receptor 1 (XCR1)-expressing conventional type-1 dendritic cells (cDC1s), which are critical in priming CD8+ cytotoxic T cells, within the TME is noticeably restricted. Hence, we present a facile methodology for the efficient fabrication of a calcium phosphate hydrogel loaded with X-C motif chemokine ligand 1 (XCL1) to selectively recruit cDC1s. Manganese phosphate microparticles were also loaded into this hydrogel to reprogram the TME via cGAS-STING activation, thereby facilitating the priming of cDC1s propelled specific CD8+ T cells. They also polarize tumor-associated macrophages towards the M1 phenotype and reduce the proportion of regulatory cells, effectively reversing the immunosuppressive TME into an immune-active one. The yielded XCL1@CaMnP gel exhibits significant efficacy in enhancing the therapeutic outcomes of radiotherapy, particularly when concurrently administered with postoperative radiotherapy, resulting in an impressive 60 % complete response rate. Such XCL1@CaMnP gel, which recruits cDC1s to present tumor antigens generated in situ, holds great potential as a versatile platform for enhanced cancer treatment through modulating the immunosuppressive TME.
    Keywords:  Calcium phosphate hydrogel; Conventional type-1 dendritic cells; Enhanced radiotherapy; Reprogramming of tumor microenvironment; cGAS-STING activation
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.122470
  19. Front Cell Infect Microbiol. 2023 ;13 1273254
    The crosstalk of intratumor bacteria and the tumor.
    Jiating Huang, Yuqin Mao, Lishun Wang.
      The in-depth studies reveal the interaction between the host and commensal microbiomes. Symbiotic bacteria influence in tumor initiation, progression, and response to treatment. Recently, intratumor bacteria have been a burgeoning research field. The tumor microenvironment is under vascular hyperplasia, aerobic glycolysis, hypoxia, and immunosuppression. It might be attractive for bacterial growth and proliferation. As a component of the tumor microenvironment, intratumor bacteria influence tumor growth and metastasis, as well as the efficacy of anti-tumor therapies. Therefore, understanding the intricate interplay of intratumoral bacteria and the host might contribute to better approaches to treat tumors. In this review, we summarize current evidence about roles of intratumor bacteria in tumor initiation and anti-tumor therapy, and what is remained to be solved in this field.
    Keywords:  bacteria; immune; intratumor; therapy; tumor
    DOI:  https://doi.org/10.3389/fcimb.2023.1273254
  20. Cancer Metastasis Rev. 2024 Jan 18.
    Epigenetic reprogramming of T cells: unlocking new avenues for cancer immunotherapy.
    Vipin Singh, Sandhik Nandi, Aritra Ghosh, Santanu Adhikary, Shravanti Mukherjee, Siddhartha Roy, Chandrima Das.
      T cells, a key component of cancer immunotherapy, undergo a variety of histone modifications and DNA methylation changes since their bone marrow progenitor stages before developing into CD8+ and CD4+ T cells. These T cell types can be categorized into distinct subtypes based on their functionality and properties, such as cytotoxic T cells (Tc), helper T cells (Th), and regulatory T cells (Treg) as subtypes for CD8+ and CD4+ T cells. Among these, the CD4+ CD25+ Tregs potentially contribute to cancer development and progression by lowering T effector (Teff) cell activity under the influence of the tumor microenvironment (TME). This contributes to the development of therapeutic resistance in patients with cancer. Subsequently, these individuals become resistant to monoclonal antibody therapy as well as clinically established immunotherapies. In this review, we delineate the different epigenetic mechanisms in cancer immune response and its involvement in therapeutic resistance. Furthermore, the possibility of epi-immunotherapeutic methods based on histone deacetylase inhibitors and histone methyltransferase inhibitors are under investigation. In this review we highlight EZH2 as the principal driver of cancer cell immunoediting and an immune escape regulator. We have addressed in detail how understanding T cell epigenetic regulation might bring unique inventive strategies to overcome drug resistance and increase the efficacy of cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Epigenetic reprogramming; T cells
    DOI:  https://doi.org/10.1007/s10555-024-10167-w
  21. J Cell Physiol. 2024 Jan 14.
    Role of the ubiquitin-proteasome system on macrophages in the tumor microenvironment.
    Yue Xiao, Ruiqian Liu, Na Li, Yong Li, Xuan Huang.
      Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment, and their different polarization states play multiple roles in tumors by secreting cytokines, chemokines, and so on, which are closely related to tumor development. In addition, the enrichment of TAMs is often associated with poor prognosis of tumors. Thus, targeting TAMs is a potential tumor treatment strategy, in which therapeutic approaches such as reducing TAMs numbers, remodeling TAMs phenotypes, and altering their functions are being extensively investigated. Meanwhile, the ubiquitin-proteasome system (UPS), an important mechanism of protein hydrolysis in eukaryotic cells, participates in cellular processes by regulating the activity and stability of key proteins. Interestingly, UPS plays a dual role in the process of tumor development, and its role in TAMs deserve to be investigated in depth. This review builds on this foundation to further explore the multiple roles of UPS on TAMs and identifies a promising approach to treat tumors by targeting TAMs with UPS.
    Keywords:  E3 ubiquitin ligase; macrophage polarization; therapy; tumor-associated macrophages; ubiquitin-proteasome system
    DOI:  https://doi.org/10.1002/jcp.31180
  22. Res Sq. 2023 Dec 26. pii: rs.3.rs-3707472. [Epub ahead of print]
    Wnt inhibition alleviates resistance to immune checkpoint blockade in glioblastoma.
    Rakesh Jain, Shanmugarajan Krishnan, Somin Lee, Zohreh Amoozgar, Sonu Subudhi, Ashwin Kumar, Jessica Posada, Neal Lindeman, Pinji Lei, Mark Duquette, Sylvie Roberge, Peigen Huang, Patrik Andersson, Meenal Datta, Lance Munn, Dai Fukumura.
      Wnt signaling plays a critical role in the progression and treatment outcome of glioblastoma (GBM). Here, we identified WNT7b as a heretofore unknown mechanism of resistance to immune checkpoint inhibition (αPD1) in GBM patients and murine models. Acquired resistance to αPD1 was found to be associated with the upregulation of Wnt7b and β-catenin protein levels in GBM in patients and in a clinically relevant, stem-rich GBM model. Combining the porcupine inhibitor WNT974 with αPD1 prolonged the survival of GBM-bearing mice. However, this combination had a dichotomous response, with a subset of tumors showing refractoriness. WNT974 and αPD1 expanded a subset of DC3-like dendritic cells (DCs) and decreased the granulocytic myeloid-derived suppressor cells (gMDSCs) in the tumor microenvironment (TME). By contrast, monocytic MDSCs (mMDSCs) increased, while T-cell infiltration remained unchanged, suggesting potential TME-mediated resistance. Our preclinical findings warrant the testing of Wnt7b/β-catenin combined with αPD1 in GBM patients with elevated Wnt7b/β-catenin signaling.
    DOI:  https://doi.org/10.21203/rs.3.rs-3707472/v1
  23. EMBO Mol Med. 2024 Jan 15.
    Bacteria colonization in tumor microenvironment creates a favorable niche for immunogenic chemotherapy.
    See-Khai Lim, Wen-Ching Lin, Sin-Wei Huang, Yi-Chung Pan, Che-Wei Hu, Chung-Yuan Mou, Che-Ming Jack Hu, Kurt Yun Mou.
      The tumor microenvironment (TME) presents differential selective pressure (DSP) that favors the growth of cancer cells, and monovalent therapy is often inadequate in reversing the cancer cell dominance in the TME. In this work, we introduce bacteria as a foreign species to the TME and explore combinatorial treatment strategies to alter DSP for tumor eradication. We show that cancer-selective chemotherapeutic agents and fasting can provide a strong selection pressure against tumor growth in the presence of bacteria. Moreover, we show that an immunogenic drug (oxaliplatin), but not a non-immunogenic one (5-FU), synergizes with the bacteria to activate both the innate and adaptive immunity in the TME, resulting in complete tumor remission and a sustained anti-tumor immunological memory in mice. The combination of oxaliplatin and bacteria greatly enhances the co-stimulatory and antigen-presenting molecules on antigen-presenting cells, which in turn bridge the cytotoxic T cells for cancer-cell killing. Our findings indicate that rational combination of bacterial therapy and immunogenic chemotherapy can promote anticancer immunity against the immunosuppressive TME.
    Keywords:  Bacteria Cancer Therapy; Differential Stress Resistance; Immunotherapy; Oxaliplatin; TME Remodeling
    DOI:  https://doi.org/10.1038/s44321-023-00022-w
  24. EMBO Mol Med. 2024 Jan 18.
    Macrophages reprogramming improves immunotherapy of IL-33 in peritoneal metastasis of gastric cancer.
    Keying Che, Yuting Luo, Xueru Song, Zhe Yang, Hanbing Wang, Tao Shi, Yue Wang, Xuan Wang, Hongyan Wu, Lixia Yu, Baorui Liu, Jia Wei.
      Peritoneal metastasis (PM) has a suppressive tumor immune microenvironment (TIME) that limits the effects of immunotherapy. This study aimed to investigate the immunomodulatory effects of intraperitoneal administration of IL-33, a cytokine that is reported to potentiate antitumor immunity and inhibit metastasis. We found survival was significantly prolonged in patients with high IL-33 mRNA expression. In immunocompetent mice, intraperitoneal administration of IL-33 could induce a celiac inflammatory environment, activate immunologic effector cells, and reverse the immunosuppressive tumor microenvironment, which effectively delayed tumor progression and PM of gastric cancer. Mechanistically, IL-33 could induce M2 polarization by activating p38-GATA-binding protein 3 signaling. IL-33 combined with anti-CSF1R or p38 inhibitor to regulate tumor-associated macrophages (TAMs) had a synergistic antitumor effect. Inducing a local inflammatory milieu by IL-33 administration provided a novel approach for treating peritoneal metastasis, which, when combined with TAM reprogramming to reshape TIME, can achieve better treatment efficacy.
    Keywords:  Gastric Cancer; IL-33; Peritoneal Metastasis; Tumor Immune Microenvironment; Tumor-associated Macrophages
    DOI:  https://doi.org/10.1038/s44321-023-00012-y
  25. Bull Math Biol. 2024 Jan 19. 86(2): 20
    Understanding the Interplay of CAR-NK Cells and Triple-Negative Breast Cancer: Insights from Computational Modeling.
    Abazar Arabameri, Samaneh Arab.
      Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells have recently emerged as a promising and safe alternative to CAR-T cells for targeting solid tumors. In the case of triple-negative breast cancer (TNBC), traditional cancer treatments and common immunotherapies have shown limited effectiveness. However, CAR-NK cells have been successfully employed to target epidermal growth factor receptor (EGFR) on TNBC cells, thereby enhancing the efficacy of immunotherapy. The effectiveness of CAR-NK-based immunotherapy is influenced by various factors, including the vaccination dose, vaccination pattern, and tumor immunosuppressive factors in the microenvironment. To gain insights into the dynamics and effects of CAR-NK-based immunotherapy, we propose a computational model based on experimental data and immunological theories. This model integrates an individual-based model that describes the interplay between the tumor and the immune system, along with an ordinary differential equation model that captures the variation of inflammatory cytokines. Computational results obtained from the proposed model shed light on the conditions necessary for initiating an effective anti-tumor response. Furthermore, global sensitivity analysis highlights the issue of low persistence of CAR-NK cells in vivo, which poses a significant challenge for the successful clinical application of these cells. Leveraging the model, we identify the optimal vaccination time, vaccination dose, and time interval between injections for maximizing therapeutic outcomes.
    Keywords:  CAR-NK; Immune system; Individual-based model; Mathematical modeling; Triple-negative breast cancer; Tumor
    DOI:  https://doi.org/10.1007/s11538-023-01247-z
  26. ACS Nano. 2024 Jan 18.
    An Adjuvant Micelle-Based Multifunctional Nanosystem for Tumor Immunotherapy by Remodeling Three Types of Immunosuppressive Cells.
    Siyu Meng, Huiping Du, Xiang Li, Xinmin Zheng, Pan Zhao, Zhang Yuan, Shaohui Huang, Yanli Zhao, Liangliang Dai.
      Immunotherapy is restricted by a complex tumor immunosuppressive microenvironment (TIM) and low drug delivery efficiency. Herein, a multifunctional adjuvant micelle nanosystem (PPD/MPC) integrated with broken barriers and re-education of three classes of immune-tolerant cells is constructed for cancer immunotherapy. The nanosystem significantly conquers the penetration barrier via the weakly acidic tumor microenvironment-responsive size reduction and charge reversal strategy. The detached core micelle MPC could effectively be internalized by tumor-associated macrophages (TAMs), tumor-infiltrating dendritic cells (TIDCs), and myeloid-derived suppressor cells (MDSCs) via mannose-mediated targeting endocytosis and electrostatic adsorption pathways, promoting the re-education of immunosuppressive cells for allowing them to reverse from pro-tumor to antitumor phenotypes by activating TLR4/9 pathways. This process in turn leads to the remodeling of TIM. In vitro and in vivo studies collectively indicate that the adjuvant micelle-based nanosystem not only relieves the intricate immune tolerance and remodels TIM via reprogramming the three types of immunosuppressive cells and regulating the secretion of relevant cytokines/immunity factors but also strengthens immune response and evokes immune memory, consequently suppressing the tumor growth and metastasis.
    Keywords:  cancer-targeted triple immunotherapy; drug delivery barriers; immune-tolerant cells; multifunctional adjuvant micelles; reprogramming tumor immunosuppressive microenvironment
    DOI:  https://doi.org/10.1021/acsnano.3c08792
  27. Heliyon. 2024 Jan 15. 10(1): e23870
    Intra-tumor ROS amplification by melatonin interferes in the apoptosis-autophagy-inflammation-EMT collusion in the breast tumor microenvironment.
    Nirmal Das, Sudeshna Mukherjee, Ankur Das, Payal Gupta, Amit Bandyopadhyay, Sreya Chattopadhyay.
      Epidemiological as well as experimental studies have established that the pineal hormone melatonin has inhibitory effects on different types of cancers. Several mechanisms have been proposed for the anticancer activities of melatonin, but the fundamental molecular pathways still require clarity. We developed a mouse model of breast cancer using Ehrlich's ascites carcinoma (injected in the 4th mammary fat pad of female Swiss albino mice) and investigated the possibility of targeting the autophagy-inflammation-EMT colloquy to restrict breast tumor progression using melatonin as intervention. Contrary to its conventional antioxidant role, melatonin was shown to augment intracellular ROS and initiate ROS-dependent apoptosis in our system, by modulating the p53/JNK & NF-κB/pJNK expressions/interactions. Melatonin-induced ROS promoted SIRT1 activity. Interplay between SIRT1 and NF-κB/p65 is known to play a pivotal role in regulating the crosstalk between autophagy and inflammation. Persistent inflammation in the tumor microenvironment and subsequent activation of the IL-6/STAT3/NF-κB feedback loop promoted EMT and suppression of autophagy through activation of PI3K/Akt/mTOR signaling pathway. Melatonin disrupted NF-κB/SIRT1 interactions blocking IL-6/STAT3/NF-κB pathway. This led to reversal of pro-inflammatory bias in the breast tumor microenvironment and augmented autophagic responses. The interactions between p62/Twist1, NF-κB/Beclin1 and NF-κB/Slug were altered by melatonin to strike a balance between autophagy, inflammation and EMT, leading to tumor regression. This study provides critical insights into how melatonin could be utilized in treating breast cancer via inhibition of the PI3K/Akt/mTOR signaling and differential modulation of SIRT1 and NF-κB proteins, leading to the establishment of apoptotic and autophagic fates in breast cancer cells.
    Keywords:  Autophagy; Breast cancer; EMT; Inflammation; Melatonin; ROS
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e23870
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