bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024‒08‒11
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.
  2. Macrophage-based cancer immunotherapy: challenges and opportunities.
  3. Intratumoral Microbiome: Foe or Friend in Reshaping the Tumor Microenvironment Landscape?
  4. Chemokines in the tumor microenvironment: implications for lung cancer and immunotherapy.
  5. Unlocking the potential: Targeting metabolic pathways in the tumor microenvironment for Cancer therapy.
  6. Blocking CX3CR1+ Tumor-associated Macrophages Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma.
  7. Extracellular vesicles reshape the tumor microenvironment to improve cancer immunotherapy: Current knowledge and future prospects.
  8. Tumor battlefield within inflamed, excluded or desert immune phenotypes: the mechanisms and strategies.
  9. Targeting myeloid-derived suppressor cells by inhibiting hypoxia-inducible factor 1α could improve tumor progression.
  10. PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer.
  11. The role of innate immune cells in the colorectal cancer tumor microenvironment and advances in anti-tumor therapy research.
  12. The next frontier in immunotherapy: potential and challenges of CAR-macrophages.
  13. Characteristics and mechanisms of T-cell senescence: A potential target for cancer immunotherapy.
  14. An Immune-Enhancing Injectable Hydrogel Loaded with Esketamine and DDP Promotes Painless Immunochemotherapy to Inhibit Breast Cancer Growth.
  15. Understanding tissue-resident macrophages unlocks the potential for novel combinatorial strategies in breast cancer.
  16. Transforming growth factor-β micro-environment mediated immune cell functions in cervical cancer.
  17. Tumor-associated macrophage clusters linked to immunotherapy in a pan-cancer census.
  18. [Adoptive cell therapy for solid tumors].
  19. Pan-cancer analysis of immune checkpoint receptors and ligands in various cells in the tumor immune microenvironment.
  20. Entering the TiME machine: How age-related changes in the tumor immune microenvironment impact melanoma progression and therapy response.
  21. Deliberation concerning the role of M1-type macrophage subset in oral carcinogenesis.
  22. Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
  1. Front Immunol. 2024 ;15 1353787
    Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.
    Andrea Nicolini, Paola Ferrari.
      Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.
    Keywords:  colorectal cancer; immunotherapy; metabolic reprogramming; tumor immune escape; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1353787
  2. Exp Cell Res. 2024 Aug 03. pii: S0014-4827(24)00289-1. [Epub ahead of print] 114198
    Macrophage-based cancer immunotherapy: challenges and opportunities.
    Haotian Bai, Li Feng, Felix Schmid.
      Macrophages play crucial roles in the tumor microenvironment (TME), exerting diverse functions ranging from promoting tumor growth and metastasis to orchestrating anti-tumor immune responses. Their plasticity allows them to adopt distinct activation states, often called M1-like (pro-inflammatory) and M2-like (anti-inflammatory or pro-tumoral), significantly influencing tumor progression and response to therapy. Harnessing the potential of macrophages in cancer immunotherapy has emerged as a promising strategy, with increasing interest in targeting these cells directly or modulating their functions within the TME. This review explores the intricate interplay between macrophages, the TME, and immunotherapeutic approaches. We discuss the dynamic phenotypic and functional heterogeneity of tumor-associated macrophages (TAMs), their impact on disease progression, and the mechanisms underlying their response to immunotherapy. Furthermore, we highlight recent advancements in macrophage-based immunotherapeutic strategies, including macrophage-targeting agents, adoptive cell transfer, and engineering approaches. Understanding the complex crosstalk between macrophages and the TME is essential for developing effective immunotherapeutic interventions that exploit the immunomodulatory functions of macrophages to enhance anti-tumor immunity and improve clinical outcomes for cancer patients.
    Keywords:  Immune responses; Immunotherapy; Macrophages; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.yexcr.2024.114198
  3. Cells. 2024 Jul 30. pii: 1279. [Epub ahead of print]13(15):
    Intratumoral Microbiome: Foe or Friend in Reshaping the Tumor Microenvironment Landscape?
    Athina A Kyriazi, Makrina Karaglani, Sofia Agelaki, Stavroula Baritaki.
      The role of the microbiome in cancer and its crosstalk with the tumor microenvironment (TME) has been extensively studied and characterized. An emerging field in the cancer microbiome research is the concept of the intratumoral microbiome, which refers to the microbiome residing within the tumor. This microbiome primarily originates from the local microbiome of the tumor-bearing tissue or from translocating microbiome from distant sites, such as the gut. Despite the increasing number of studies on intratumoral microbiome, it remains unclear whether it is a driver or a bystander of oncogenesis and tumor progression. This review aims to elucidate the intricate role of the intratumoral microbiome in tumor development by exploring its effects on reshaping the multileveled ecosystem in which tumors thrive, the TME. To dissect the complexity and the multitude of layers within the TME, we distinguish six specialized tumor microenvironments, namely, the immune, metabolic, hypoxic, acidic, mechanical and innervated microenvironments. Accordingly, we attempt to decipher the effects of the intratumoral microbiome on each specialized microenvironment and ultimately decode its tumor-promoting or tumor-suppressive impact. Additionally, we portray the intratumoral microbiome as an orchestrator in the tumor milieu, fine-tuning the responses in distinct, specialized microenvironments and remodeling the TME in a multileveled and multifaceted manner.
    Keywords:  cancer; immune cells; metabolism; microbiome; therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells13151279
  4. Front Immunol. 2024 ;15 1443366
    Chemokines in the tumor microenvironment: implications for lung cancer and immunotherapy.
    Haebeen Jung, Silke Paust.
      The tumor microenvironment (TME) is a complex interconnected network of immune cells, fibroblasts, blood vessels, and extracellular matrix surrounding the tumor. Because of its immunosuppressive nature, the TME can pose a challenge for cancer immunotherapies targeting solid tumors. Chemokines have emerged as a crucial element in enhancing the efficacy of cancer immunotherapy, playing a direct role in immune cell signaling within the TME and facilitating immune cell migration towards cancer cells. However, chemokine ligands and their receptors exhibit context-dependent diversity, necessitating evaluation of their tumor-promoting or inhibitory effects based on tumor type and immune cell characteristics. This review explores the role of chemokines in tumor immunity and metastasis in the context of the TME. We also discuss current chemokine-related advances in cancer immunotherapy research, with a particular focus on lung cancer, a common cancer with a low survival rate and limited immunotherapy options.
    Keywords:  cancer; chemokines; immune cells; immunotherapy; lung cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1443366
  5. Biochim Biophys Acta Rev Cancer. 2024 Aug 05. pii: S0304-419X(24)00097-0. [Epub ahead of print] 189166
    Unlocking the potential: Targeting metabolic pathways in the tumor microenvironment for Cancer therapy.
    Siyuan Jia, Ann M Bode, Xue Chen, Xiangjian Luo.
      Cancer incidence and mortality are increasing and impacting global life expectancy. Metabolic reprogramming in the tumor microenvironment (TME) is intimately related to tumorigenesis, progression, metastasis and drug resistance. Tumor cells drive metabolic reprogramming of other cells in the TME through metabolic induction of cytokines and metabolites, and metabolic substrate competition. Consequently, this boosts tumor cell growth by providing metabolic support and facilitating immunosuppression and angiogenesis. The metabolic interplay in the TME presents potential therapeutic targets. Here, we focus on the metabolic reprogramming of four principal cell subsets in the TME: CAFs, TAMs, TILs and TECs, and their interaction with tumor cells. We also summarize medications and therapies targeting these cells' metabolic pathways, particularly in the context of immune checkpoint blockade therapy.
    Keywords:  Cancer-associated fibroblasts (CAFs); Immune check point blockade (ICB); Metabolic reprogramming; Tumor endothelial cells (TECs); Tumor microenvironment (TME); Tumor-associated macrophages (TAMs); Tumor-infiltrating lymphocytes (TILs) therapy
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189166
  6. Cancer Immunol Res. 2024 Aug 08.
    Blocking CX3CR1+ Tumor-associated Macrophages Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma.
    Xiaonan Xiang, Kai Wang, Hui Zhang, Haibo Mou, Zhixiong Shi, Yaoye Tao, Hongliang Song, Zhengxing Lian, Shuai Wang, Di Lu, Xuyong Wei, Haiyang Xie, Shusen Zheng, Jianguo Wang, Xiao Xu.
      The efficacy of immune checkpoint inhibitors (ICI) in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the underlying mechanisms. Accumulating evidence indicates that tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) are implicated in immune evasion and treatment resistance. This study aimed to explore the contribution of TAMs in the HCC TME. Our findings reveal the critical involvement of CX3C motif chemokine receptor 1 (CX3CR1)-positive TAMs in inducing T cell exhaustion through interleukin-27 (IL-27) secretion, providing valuable insights into the mechanisms underlying the suboptimal efficacy of anti-PD-1 therapy in HCC. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of CX3CR1+ TAM phenotype transition. To augment the therapeutic response to current anti-PD-1 therapy, we propose an innovative treatment strategy that incorporates targeting CX3CR1+ TAMs in addition to anti-PD-1 therapy. In conclusion, our study contributes to the understanding of TAMs' role in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD-1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in HCC patients.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0627
  7. Int Immunopharmacol. 2024 Aug 02. pii: S1567-5769(24)01341-9. [Epub ahead of print]140 112820
    Extracellular vesicles reshape the tumor microenvironment to improve cancer immunotherapy: Current knowledge and future prospects.
    Yu Hang, JingYi Huang, Mingming Ding, Yanhua Shen, YaoZhong Zhou, Wan Cai.
      Tumor immunotherapy has revolutionized cancer treatment, but limitations remain, including low response rates and immune complications. Extracellular vesicles (EVs) are emerging as a new class of therapeutic agents for various diseases. Recent research shows that changes in the amount and composition of EVs can reshape the tumor microenvironment (TME), potentially improving the effectiveness of immunotherapy. This exciting discovery has sparked clinical interest in using EVs to enhance the immune system's response to cancer. In this Review, we delve into the world of EVs, exploring their origins, how they're generated, and their complex interactions within the TME. We also discuss the crucial role EVs play in reshaping the TME during tumor development. Specifically, we examine how their cargo, including molecules like PD-1 and non-coding RNA, influences the behavior of key immune cells within the TME. Additionally, we explore the current applications of EVs in various cancer therapies, the latest advancements in engineering EVs for improved immunotherapy, and the challenges faced in translating this research into clinical practice. By gaining a deeper understanding of how EVs impact the TME, we can potentially uncover new therapeutic vulnerabilities and significantly enhance the effectiveness of existing cancer immunotherapies.
    Keywords:  Cancer immunotherapy; Engineered EVs; Extracellular vesicles; PD-1; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.112820
  8. Exp Hematol Oncol. 2024 Aug 06. 13(1): 80
    Tumor battlefield within inflamed, excluded or desert immune phenotypes: the mechanisms and strategies.
    Siwei Zheng, Wenwen Wang, Lesang Shen, Yao Yao, Wenjie Xia, Chao Ni.
      The tumor microenvironment demonstrates great immunophenotypic heterogeneity, which has been leveraged in traditional immune-hot/cold tumor categorization based on the abundance of intra-tumoral immune cells. By incorporating the spatial immune contexture, the tumor immunophenotype was further elaborated into immune-inflamed, immune-excluded, and immune-desert. However, the mechanisms underlying these different immune phenotypes are yet to be comprehensively elucidated. In this review, we discuss how tumor cells and the tumor microenvironment interact collectively to shape the immune landscape from the perspectives of tumor cells, immune cells, the extracellular matrix, and cancer metabolism, and we summarize potential therapeutic options according to distinct immunophenotypes for personalized precision medicine.
    Keywords:  Immunotherapy; Tumor immune phenotype; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40164-024-00543-1
  9. Ann Med Surg (Lond). 2024 Aug;86(8): 4449-4455
    Targeting myeloid-derived suppressor cells by inhibiting hypoxia-inducible factor 1α could improve tumor progression.
    Qiying Xu, Huifang Liu, Xiaoyan Song, Tana Wuren, Ri-Li Ge.
      Myeloid-derived suppressor cells (MDSCs) are a subset of immature myeloid cells that inhibit anti-tumor immunity and contribute to poor cancer outcomes. In this study, the authors used multi-color flow cytometry to detect changes in MDSCs in patients with cancer and tumor-bearing mice. Then the authors studied changes in MDSCs ratio and mouse tumors after administration of hypoxia-inducible factor 1α (HIF-1α) inhibitor. The results showed that the ratio of MDSCs, specifically polymorphonuclear MDSCs (PMN-MDSCs), was higher in patients with cancer, and both PMN-MDSCs and monocytic MDSCs (M-MDSCs) ratio were higher in tumor-bearing mice. When provided with the HIF-1α inhibitor LW-6, the ratio of MDSCs decreased in tumor-bearing mice, particularly PMN-MDSCs, and the volume of liver metastases also decreased. The authors' findings suggest that reducing MDSCs by inhibiting hypoxia-inducible factor 1α may slow tumor progression.
    Keywords:  LW-6; cancer outcomes; hypoxia-inducible factor 1 α; myeloid-derived suppressor cells; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000002126
  10. Angiogenesis. 2024 Aug 08.
    PDPN/CCL2/STAT3 feedback loop alter CAF heterogeneity to promote angiogenesis in colorectal cancer.
    Die Yu, Hanzheng Xu, Jinzhe Zhou, Kai Fang, Zekun Zhao, Ke Xu.
      Colorectal cancer (CRC) is one of the common clinical malignancies and the fourth leading cause of cancer-related death in the world. The tumor microenvironment (TME) plays a crucial role in promoting tumor angiogenesis, and cancer-associated fibroblasts (CAFs) are one of the key components of the tumor microenvironment. However, due to the high heterogeneity of CAFs, elucidating the molecular mechanism of CAF-mediated tumor angiogenesis remained elusive. In our study, we found that there is pro-angiogenic functional heterogeneity of CAFs in colorectal cancer and we clarified that Podoplanin (PDPN) can specifically label CAF subpopulations with pro-angiogenic functions. We also revealed that PDPN + CAF could maintain CAF heterogeneity by forming a PDPN/CCL2/STAT3 feedback loop through autocrine CCL2, while activate STAT3 signaling pathway in endothelial cells to promote angiogenesis through paracrine CCL2. We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.
    Keywords:  Angiogenesis; CAF; CRC; PDPN; STAT3
    DOI:  https://doi.org/10.1007/s10456-024-09941-9
  11. Front Immunol. 2024 ;15 1407449
    The role of innate immune cells in the colorectal cancer tumor microenvironment and advances in anti-tumor therapy research.
    Wenxuan Liu, Tianrui Kuang, Li Liu, Wenhong Deng.
      Innate immune cells in the colorectal cancer microenvironment mainly include macrophages, neutrophils, natural killer cells, dendritic cells and bone marrow-derived suppressor cells. They play a pivotal role in tumor initiation and progression through the secretion of diverse cytokines, chemokines, and other factors that govern these processes. Colorectal cancer is a common malignancy of the gastrointestinal tract, and understanding the role of innate immune cells in the microenvironment of CRC may help to improve therapeutic approaches to CRC and increase the good prognosis. In this review, we comprehensively explore the pivotal role of innate immune cells in the initiation and progression of colorectal cancer (CRC), alongside an extensive evaluation of the current landscape of innate immune cell-based immunotherapies, thereby offering valuable insights for future research strategies and clinical trials.
    Keywords:  colorectal cancer; immune cell; immunotherapy; innate immune cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1407449
  12. Exp Hematol Oncol. 2024 Aug 05. 13(1): 76
    The next frontier in immunotherapy: potential and challenges of CAR-macrophages.
    Jing Li, Ping Chen, Wenxue Ma.
      Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages' phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.
    Keywords:  CAR macrophage (CAR-MΦ); Clinical trials; Combination therapies; Immunotherapy; Tumor Microenvironment (TME)
    DOI:  https://doi.org/10.1186/s40164-024-00549-9
  13. Eur J Immunol. 2024 Aug 06. e2451093
    Characteristics and mechanisms of T-cell senescence: A potential target for cancer immunotherapy.
    Han Wu, Junru Li, Zhen Zhang, Yi Zhang.
      Immunosenescence, the aging of the immune system, leads to functional deficiencies, particularly in T cells, which undergo significant changes. While numerous studies have investigated age-related T-cell phenotypes in healthy aging, senescent T cells have also been observed in younger populations during pathological conditions like cancer. This review summarizes the recent advancements in age-associated alterations and markers of T cells, mechanisms, and the relationship between senescent T cells and the tumor microenvironment. We also discuss potential strategies for targeting senescent T cells to prevent age-related diseases and enhance tumor immunotherapy efficacy.
    Keywords:  Aging; Immunotherapy; Tumor microenvironment; T‐cell senescence
    DOI:  https://doi.org/10.1002/eji.202451093
  14. Adv Healthc Mater. 2024 Aug 09. e2401373
    An Immune-Enhancing Injectable Hydrogel Loaded with Esketamine and DDP Promotes Painless Immunochemotherapy to Inhibit Breast Cancer Growth.
    Xiali Yin, Yaohua Ke, Ying Liang, Shuxian Zhang, Ziqi Chen, Lixia Yu, Ming Jiang, Qin Liu, Xiaoping Gu.
      Chemotherapy is the cornerstone of triple-negative breast cancer. The poor effectiveness and severe neuropathic pain caused by it have a significant impact on the immune system. Studies confirmed that immune cells in the tumor microenvironment (TME), have critical roles in tumor immune regulation and prognosis. In this study, it is revealed that the painless administration of Esketamine, combined with Cisplatin (DDP), can exert an anti-tumor effect, which is further boosted by the hydrogel delivery system. It is also discovered that Esketamine combined with DDP co-loaded in Poloxamer Hydrogel (PDEH) induces local immunity by increasing mature Dendritic Cells (mDCs) and activated T cells in PDEH group while the regulatory T cells (Tregs) known as CD4+CD25+FoxP3+decreased significantly. Finally, , CD8+ and CD4+ T cells in the spleen exhibited a significant increase, suggesting a lasting immune impact of PDEH. This study proposes that Esketamine can serve as a painless immune modulator, enhancing an anti-tumor effect while co-loaded in poloxamer hydrogel with DDP. Along with improving immune cells in the microenvironment, it can potentially alleviate anxiety and depression. With its outstanding bio-safety profile, it offers promising new possibilities for painless clinical therapy.
    Keywords:  breast cancer; esketamine; injectable hydrogel; local immune; tumor microenvironment
    DOI:  https://doi.org/10.1002/adhm.202401373
  15. Front Immunol. 2024 ;15 1375528
    Understanding tissue-resident macrophages unlocks the potential for novel combinatorial strategies in breast cancer.
    Manjusha Biswas.
      Tissue-resident macrophages (TRMs) are an integral part of the innate immune system, but their biology is not well understood in the context of cancer. Distinctive resident macrophage populations are identified in different organs in mice using fate mapping studies. They develop from the yolk sac and self-maintain themselves lifelong in specific tissular niches. Similarly, breast-resident macrophages are part of the mammary gland microenvironment. They reside in the breast adipose tissue stroma and close to the ductal epithelium and help in morphogenesis. In breast cancer, TRMs may promote disease progression and metastasis; however, precise mechanisms have not been elucidated. TRMs interact intimately with recruited macrophages, cytotoxic T cells, and other immune cells along with cancer cells, deciding further immunosuppressive or cytotoxic pathways. Moreover, triple-negative breast cancer (TNBC), which is generally associated with poor outcomes, can harbor specific TRM phenotypes. The influence of TRMs on adipose tissue stroma of the mammary gland also contributes to tumor progression. The complex crosstalk between TRMs with T cells, stroma, and breast cancer cells can establish a cascade of downstream events, understanding which can offer new insight for drug discovery and upcoming treatment choices. This review aims to acknowledge the previous research done in this regard while exploring existing research gaps and the future therapeutic potential of TRMs as a combination or single agent in breast cancer.
    Keywords:  breast cancer; immunotherapy; macrophage ontogeny; tissue resident macrophage; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1375528
  16. Int Immunopharmacol. 2024 Aug 06. pii: S1567-5769(24)01358-4. [Epub ahead of print]140 112837
    Transforming growth factor-β micro-environment mediated immune cell functions in cervical cancer.
    Jayapradha Gnanagurusamy, Sneha Krishnamoorthy, Sridhar Muthusami.
      Propensity to develop cervical cancer (CC) in human papilloma virus (HPV) infected individual could potentially involve the impaired immune functioning. Several stages of HPV surveillance by immune cells in tumor micro-environment (TME) is regulated mainly by transforming growth factor-beta (TGF-β) and is crucial for the establishment of CC. The role of TGF-β in the initiation and progression of CC is very complex and involve different suppressor of mothers against decapentaplegic homolog (SMAD) dependent and SMAD independent signaling mechanism(s). This review summarizes the handling of HPV by immune cells such as T lymphocytes, B lymphocytes, natural killer cells (NK), dendritic cells (DC), monocytes, macrophages, myeloid derived suppressor cells (MDSC) and their regulation by TGF-β. The hijack mechanisms adapted by HPV to evade this surveillance process is discussed. Biomarkers indicating the stages of CC and immune checkpoints that can be targeted for improved outcome are included for immune-based theragnostics. This review also addresses the direct actions of TGF-β on CC cells and tumor/immune cell interactions. Therapies focused on targeting TGF-β using small molecule inhibitors, monoclonal antibodies and TGF-β chimeric antigen receptor (CAR)T cells are collated to understand the current strategies related to TGF-β in the management of CC.
    Keywords:  Cervical cancer; Immune cells; Immuno-therapy; TGF-β; TGFβR
    DOI:  https://doi.org/10.1016/j.intimp.2024.112837
  17. NPJ Precis Oncol. 2024 Aug 09. 8(1): 176
    Tumor-associated macrophage clusters linked to immunotherapy in a pan-cancer census.
    Chen Wei, Yijie Ma, Mengyu Wang, Siyi Wang, Wenyue Yu, Shuailei Dong, Wenying Deng, Liangyu Bie, Chi Zhang, Wei Shen, Qingxin Xia, Suxia Luo, Ning Li.
      Transcriptional heterogeneity of tumor-associated macrophages (TAMs) has been investigated in individual cancers, but the extent to which these states transcend tumor types and represent a general feature of cancer remains unclear. We performed pan-cancer single-cell RNA sequencing analysis across nine cancer types and identified distinct monocyte/TAM composition patterns. Using spatial analysis from clinical study tissues, we assessed TAM functions in shaping the tumor microenvironment (TME) and influencing immunotherapy. Two specific TAM clusters (pro-inflammatory and pro-tumor) and four TME subtypes showed distinct immunological features, genomic profiles, immunotherapy responses, and cancer prognosis. Pro-inflammatory TAMs resided in immune-enriched niches with exhausted CD8+ T cells, while pro-tumor TAMs were restricted to niches associated with a T-cell-excluded phenotype and hypoxia. We developed a machine learning model to predict immune checkpoint blockade response by integrating TAMs and clinical data. Our study comprehensively characterizes the common features of TAMs and highlights their interaction with the TME.
    DOI:  https://doi.org/10.1038/s41698-024-00660-4
  18. Rinsho Ketsueki. 2024 ;65(7): 652-661
    [Adoptive cell therapy for solid tumors].
    Kenichi Sakamoto, Shigeki Yagyu.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for refractory/relapsed (R/R) hematologic malignancies, with six products approved for B-cell tumors and multiple myeloma as of the end of 2023. However, adoptive cell therapy (ACT) for solid tumors is hindered by critical challenges in multiple areas, including (1) lack of appropriate tumor-specific antigens, (2) inefficient T-cell trafficking and infiltration into the tumor microenvironment, and (3) immunosuppressive signals within the tumor milieu that induce T-cell dysfunction. This review examines the existing clinical trial data on ACT for solid tumors to elucidate the current landscape of ACT development for solid tumors. It also outlines the trajectory of ACT for solid tumors and integrative approaches to overcoming the complex tumor microenvironment.
    Keywords:  Adoptive cell therapy; Chimeric antigen receptor; Solid tumor; T cell receptor
    DOI:  https://doi.org/10.11406/rinketsu.65.652
  19. Aging (Albany NY). 2024 Aug 07. 16
    Pan-cancer analysis of immune checkpoint receptors and ligands in various cells in the tumor immune microenvironment.
    Jiahuan Jiang, Yazhang Xu, Di Chen, Jiaxin Li, Xiaoling Zhu, Jun Pan, Leyi Zhang, Pu Cheng, Jian Huang.
      Drugs that target immune checkpoint have become the most popular weapon in cancer immunotherapy, yet only have practical benefits for a small percentage of patients. Tumor cells constantly interact with their microenvironment, which is made up of a variety of immune cells as well as endothelial cells and fibroblasts. Immune checkpoint expression and blocked signaling of immune cells in the tumor microenvironment (TME) are key to tumor progression. In this study, we perform deliberation convolution on the TCGA database for human lung, breast, and colorectal cancer to infer crosstalk between immune checkpoint receptors (ICRs) and ligands (ICLs) in TME of pan-carcinogenic solid tumor types, validated by flow cytometry. Analysis of immune checkpoints showed that there was little variation between different tumor types. It showed that CD160, LAG3, TIGIT were found to be highly expressed in CD8+ T cells instead of CD4+ T cells, PD-L1, PD-L2, CD86, LGALS9, TNFRSF14, LILRB4 and other ligands were highly expressed on macrophages, FVR, NECTIN2, FGL1 were highly expressed on Epithelial cells, CD200 was highly expressed in Endothelial cells, and CD80 was highly expressed in CD8 High expression on T cells. Overall, our study provides a new resource for the expression of immune checkpoints in TME on various types of cells. Significance: This study provides immune checkpoint expression of immune cells of multiple cancer types to infer immune mechanisms in the tumor microenvironment and provide ideas for the development of new immune checkpoint-blocking drugs.
    Keywords:  ICLs; ICRs; pan-cancer analysis; tumor immune microenvironment
    DOI:  https://doi.org/10.18632/aging.206053
  20. Pharmacol Ther. 2024 Aug 03. pii: S0163-7258(24)00118-9. [Epub ahead of print]262 108698
    Entering the TiME machine: How age-related changes in the tumor immune microenvironment impact melanoma progression and therapy response.
    Alexis E Carey, Ashani T Weeraratna.
      Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.
    Keywords:  Aging; Cancer; Immunology; Immunotherapy; Melanoma
    DOI:  https://doi.org/10.1016/j.pharmthera.2024.108698
  21. J Exp Clin Cancer Res. 2024 Aug 08. 43(1): 220
    Deliberation concerning the role of M1-type macrophage subset in oral carcinogenesis.
    Chen-Xi Li, Zhong-Cheng Gong, Jing-Wen Yu.
      Over the last decade, accumulating evidence has suggested that tumor-associated macrophages (TAMs) play a significant role in the tumor development. This commentary wishes to highlight the findings by You, et al. that M1-like TAMs could cascade a mesenchymal/stem-like phenotype of oral squamous cell carcinoma (OSCC) via the IL6/Stat3/THBS1 feedback loop. These unprecedented findings identified M1-like TAMs-regulated processes as potentially tumor-promotion in the context of OSCC immunomicroenvironment.
    Keywords:   Porphyromonas gingivalis ; M1–M2 macrophage polarization; Oral squamous cell carcinoma; Tumor-associated macrophages
    DOI:  https://doi.org/10.1186/s13046-024-03128-2
  22. Am J Physiol Cell Physiol. 2024 Aug 05.
    Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
    Michala G Rolver, Marc Severin, Stine F Pedersen.
      The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increases susceptibility to oxidative stress, lipotoxicity and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions as well as of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.
    Keywords:  ferroptosis; lipid metabolism; mitochondria; oxidative phosphorylation; peroxisomes
    DOI:  https://doi.org/10.1152/ajpcell.00429.2024
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