bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–10–13
seven papers selected by
Oltea Sampetrean, Keio University
  1. Lipids in the tumor microenvironment: immune modulation and metastasis.
  2. Metabolism and macrophages in the tumor microenvironment.
  3. Histone lactylation drives CD8+ T cell metabolism and function.
  4. GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
  5. Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors.
  6. Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.
  7. Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer.
  1. Front Oncol. 2024 ;14 1435480
    Lipids in the tumor microenvironment: immune modulation and metastasis.
    Gloria Pascual, Salvador Aznar Benitah.
      Tumor cells can undergo metabolic adaptations that support their growth, invasion, and metastasis, such as reprogramming lipid metabolism to meet their energy demands and to promote survival in harsh microenvironmental conditions, including hypoxia and acidification. Metabolic rewiring, and especially alterations in lipid metabolism, not only fuel tumor progression but also influence immune cell behavior within the tumor microenvironment (TME), leading to immunosuppression and immune evasion. These processes, in turn, may contribute to the metastatic spread of cancer. The diverse metabolic profiles of immune cell subsets, driven by the TME and tumor-derived signals, contribute to the complex immune landscape in tumors, affecting immune cell activation, differentiation, and effector functions. Understanding and targeting metabolic heterogeneity among immune cell subsets will be crucial for developing effective cancer immunotherapies that can overcome immune evasion mechanisms and enhance antitumor immunity.
    Keywords:  cancer immunotherapy; lipid metabolism; metabolic adaptations; tumor metabolism; tumor micreoenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2024.1435480
  2. Curr Opin Immunol. 2024 Oct 04. pii: S0952-7915(24)00081-5. [Epub ahead of print]91 102491
    Metabolism and macrophages in the tumor microenvironment.
    Hannah Yang, Chan Kim, Weiping Zou.
      Tumor-associated macrophages (TAMs) constitute the primary subset of immune cells within the tumor microenvironment (TME). Exhibiting both phenotypic and functional heterogeneity, TAMs play distinct roles in tumor initiation, progression, and responses to therapy in patients with cancer. In response to various immune and metabolic cues within the TME, TAMs dynamically alter their metabolic profiles to adapt. Changes in glucose, amino acid, and lipid metabolism in TAMs, as well as their interaction with oncometabolites, not only sustain their energy demands but also influence their impact on tumor immune responses. Understanding the molecular mechanisms underlying the metabolic reprogramming of TAMs and their orchestration of metabolic processes can offer insights for the development of novel cancer immunotherapies targeting TAMs. Here, we discuss how metabolism reprograms macrophages in the TME and review clinical trials aiming to normalize metabolic alterations in TAMs and alleviate TAM-mediated immune suppression and protumor activity.
    DOI:  https://doi.org/10.1016/j.coi.2024.102491
  3. Nat Immunol. 2024 Oct 07.
    Histone lactylation drives CD8+ T cell metabolism and function.
    Deblina Raychaudhuri, Pratishtha Singh, Bidisha Chakraborty, Mercedes Hennessey, Aminah J Tannir, Shrinidhi Byregowda, Seanu Meena Natarajan, Abel Trujillo-Ocampo, Jin Seon Im, Sangeeta Goswami.
      The activation and functional differentiation of CD8+ T cells are linked to metabolic pathways that result in the production of lactate. Lactylation is a lactate-derived histone post-translational modification; however, the relevance of histone lactylation in the context of CD8+ T cell activation and function is not known. Here, we show the enrichment of H3K18 lactylation (H3K18la) and H3K9 lactylation (H3K9la) in human and mouse CD8+ T cells, which act as transcription initiators of key genes regulating CD8+ T cell function. Further, we note distinct patterns of H3K18la and H3K9la in CD8+ T cell subsets linked to their specific metabolic profiles. Additionally, we find that modulation of H3K18la and H3K9la by targeting metabolic and epigenetic pathways influence CD8+ T cell effector function, including antitumor immunity, in preclinical models. Overall, our study uncovers the potential roles of H3K18la and H3K9la in CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01985-9
  4. Nat Commun. 2024 Oct 06. 15(1): 8658
    GLUT1 overexpression in CAR-T cells induces metabolic reprogramming and enhances potency.
    Justin A Guerrero, Dorota D Klysz, Yiyun Chen, Meena Malipatlolla, Jameel Lone, Carley Fowler, Lucille Stuani, Audre May, Malek Bashti, Peng Xu, Jing Huang, Basil Michael, Kévin Contrepois, Shaurya Dhingra, Chris Fisher, Katrin J Svensson, Kara L Davis, Maya Kasowski, Steven A Feldman, Elena Sotillo, Crystal L Mackall.
      The intensive nutrient requirements needed to sustain T cell activation and proliferation, combined with competition for nutrients within the tumor microenvironment, raise the prospect that glucose availability may limit CAR-T cell function. Here, we seek to test the hypothesis that stable overexpression (OE) of the glucose transporter GLUT1 in primary human CAR-T cells would improve their function and antitumor potency. We observe that GLUT1OE in CAR-T cells increases glucose consumption, glycolysis, glycolytic reserve, and oxidative phosphorylation, and these effects are associated with decreased T cell exhaustion and increased Th17 differentiation. GLUT1OE also induces broad metabolic reprogramming associated with increased glutathione-mediated resistance to reactive oxygen species, and increased inosine accumulation. When challenged with tumors, GLUT1OE CAR-T cells secrete more proinflammatory cytokines and show enhanced cytotoxicity in vitro, and demonstrate superior tumor control and persistence in mouse models. Our collective findings support a paradigm wherein glucose availability is rate limiting for effector CAR-T cell function and demonstrate that enhancing glucose availability via GLUT1OE could augment antitumor immune function.
    DOI:  https://doi.org/10.1038/s41467-024-52666-y
  5. Proc Natl Acad Sci U S A. 2024 Oct 15. 121(42): e2317694121
    Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors.
    Caroline K McGuire, Ambryn S Meehan, Evan Couser, Lois Bull, Allegra C Minor, Alexandra Kuhlmann-Hogan, Susan M Kaech, Reuben J Shaw, Lillian J Eichner.
      Histone Deacetylase 3 (HDAC3) function in vivo is nuanced and directed in a tissue-specific fashion. The importance of HDAC3 in Kras mutant lung tumors has recently been identified, but HDAC3 function in this context remains to be fully elucidated. Here, we identified HDAC3 as a lung tumor cell-intrinsic transcriptional regulator of the tumor immune microenvironment. In Kras mutant lung cancer cells, we found that HDAC3 is a direct transcriptional repressor of a cassette of secreted chemokines, including Cxcl10. Genetic and pharmacological inhibition of HDAC3 robustly up-regulated this gene set in human and mouse Kras, LKB1 (KL) and Kras, p53 (KP) mutant lung cancer cells through an NF-κB/p65-dependent mechanism. Using genetically engineered mouse models, we found that HDAC3 inactivation in vivo induced expression of this gene set selectively in lung tumors and resulted in enhanced T cell recruitment at least in part via Cxcl10. Furthermore, we found that inhibition of HDAC3 in the presence of Kras pathway inhibitors dissociated Cxcl10 expression from that of immunosuppressive chemokines and that combination treatment of entinostat with trametinib enhanced T cell recruitment into lung tumors in vivo. Finally, we showed that T cells contribute to in vivo tumor growth control in the presence of entinostat and trametinib combination treatment. Together, our findings reveal that HDAC3 is a druggable endogenous repressor of T cell recruitment into Kras mutant lung tumors.
    Keywords:  Histone Deacetylase 3; KRAS mutant lung cancer; NF-κB p65; T cell recruitment; tumor immune microenvironment
    DOI:  https://doi.org/10.1073/pnas.2317694121
  6. Small. 2024 Oct 10. e2406870
    Tumor-Selective Nano-Dispatcher Enforced Cancer Immunotherapeutic Effects via Regulating Lactate Metabolism and Activating Toll-Like Receptors.
    Yang Liu, Hui Li, Yan-Yun Hao, Ling-Ling Huang, Xia Li, Jing Zou, Shi-Ying Zhang, Xiao-Yue Yang, Hong-Fei Chen, Yi-Xuan Guo, Yun-Yan Guan, Zhi-Yue Zhang.
      The development of tumors relies on lactate metabolic reprogramming to facilitate their unchecked growth and evade immune surveillance. This poses a significant challenge to the efficacy of antitumor immunity. To address this, a tumor-selective nano-dispatcher, PIMDQ/Syro-RNP, to enforce the immunotherapeutic effect through regulation of lactate metabolism and activation of toll-like receptors is developed. By using the tumor-targeting properties of c-RGD, the system can effectively deliver monocarboxylate transporters 4 (MCT4) inhibitor (Syro) to inhibit lactate efflux in tumor cells, leading to decreased lactate levels in the tumor microenvironment (TME) and increased accumulation within tumor cells. The reduction of lactate in TME will reduce the nutritional support for regulatory T cells (Tregs) and promote the effector function of T cells. The accumulation of lactate in tumor cells will lead to tumor death due to cellular acidosis. In addition, it will also reduce the uptake of glucose by tumor cells, reduce nutrient plunder, and further weaken the inhibition of T cell function. Furthermore, the pH-responsive release of Toll-like receptors (TLR) 7/8 agonist IMDQ within the TME activates dendritic cells (DCs) and promotes the infiltration of T cells. These findings offer a promising approach for enhancing tumor immune response through targeted metabolic interventions.
    Keywords:  TLR7/8; immune therapy; lactate metabolism; monocarboxylate transporters 4 (MCT4); nano‐dispatcher
    DOI:  https://doi.org/10.1002/smll.202406870
  7. J Exp Clin Cancer Res. 2024 Oct 10. 43(1): 284
    Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer.
    Yuanyuan Zheng, Lifeng Li, Zhibo Shen, Longhao Wang, Xiaoyu Niu, Yujie Wei, Shilong Sun, Jie Zhao.
       BACKGROUND: Current evidence underlines the active role of neural infiltration and axonogenesis within the tumor microenvironment (TME), with implications for tumor progression. Infiltrating nerves stimulate tumor growth and dissemination by secreting neurotransmitters, whereas tumor cells influence nerve growth and differentiation through complex interactions, promoting tumor progression. However, the role of neural infiltration in the progression of non-small cell lung cancer (NSCLC) remains unclear.
    METHODS: This study employs the techniques of immunohistochemistry, immunofluorescence, RNA sequencing, molecular biology experiments, and a murine orthotopic lung cancer model to deeply analyze the specific mechanisms behind the differential efficacy of NSCLC immunotherapy from the perspectives of neuro-tumor signal transduction, tumor metabolism, and tumor immunity.
    RESULTS: This study demonstrates that nerve growth factor (NGF) drives neural infiltration in NSCLC, and 5-hydroxytryptamine (5-HT), which is secreted by nerves, is significantly elevated in tumors with extensive neural infiltration. Transcriptome sequencing revealed that 5-HT enhanced glycolysis in NSCLC cells. Pathway analysis indicated that 5-HT activated the PI3K/Akt/mTOR pathway, promoting tumor metabolic reprogramming. This reprogramming exacerbated immunosuppression in the TME. Neutralizing 5-HT-mediated metabolic reprogramming in tumor immunity enhanced the efficacy of PD-1 monoclonal antibody treatment in mice.
    CONCLUSIONS: The findings of this study provide a novel perspective on the crosstalk between nerves and lung cancer cells and provide insights into further investigations into the role of nerve infiltration in NSCLC progression.
    Keywords:  5-hydroxytryptamine; Neural infiltration; Non-small cell lung cancer; Tumor metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-024-03202-9
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