bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–02–04
seven papers selected by
Oltea Sampetrean, Keio University
  1. Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?
  2. Tumor cell metabolic reprogramming and hypoxic immunosuppression: driving carcinogenesis to metastatic colonization.
  3. Metabolic reprogramming in the tumor microenvironment of liver cancer.
  4. Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
  5. Multimodal immune phenotyping reveals microbial-T cell interactions that shape pancreatic cancer.
  6. Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy.
  7. Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.
  1. FASEB J. 2024 Feb 15. 38(3): e23450
    Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?
    Chengcheng Peng, Pengpeng Xiao, Nan Li.
      Oncolytic virus immunotherapy as a new tumor therapy has made remarkable achievements in clinical practice. And metabolic reprogramming mediated by oncolytic virus has a significant impact on the immune microenvironment. This review summarized the reprogramming of host cell glucose metabolism, lipid metabolism, oxidative phosphorylation, and glutamine metabolism by oncolytic virus and illustrated the effects of metabolic reprogramming on the immune microenvironment. It was found that oncolytic virus-induced reprogramming of glucose metabolism in tumor cells has both beneficial and detrimental effects on the immune microenvironment. In addition, oncolytic virus can promote fatty acid synthesis in tumor cells, inhibit oxidative phosphorylation, and promote glutamine catabolism, which facilitates the anti-tumor immune function of immune cells. Therefore, targeted metabolic reprogramming is a new direction to improve the efficacy of oncolytic virus immunotherapy.
    Keywords:  glucose metabolism; glutamine metabolism; immune microenvironment; lipid metabolism; metabolic reprogramming; oncolytic virus; oxidative phosphorylation
    DOI:  https://doi.org/10.1096/fj.202301947RR
  2. Front Immunol. 2023 ;14 1325360
    Tumor cell metabolic reprogramming and hypoxic immunosuppression: driving carcinogenesis to metastatic colonization.
    Theodora Katopodi, Savvas Petanidis, Doxakis Anestakis, Charalampos Charalampidis, Ioanna Chatziprodromidou, George Floros, Panagiotis Eskitzis, Paul Zarogoulidis, Charilaos Koulouris, Christina Sevva, Konstantinos Papadopoulos, Marios Dagher, Vasileios Alexandros Karakousis, Nikolaos Varsamis, Vasiliki Theodorou, Chrysi Maria Mystakidou, Konstantinos Vlassopoulos, Stylianos Kosmidis, Nikolaos Iason Katsios, Konstantinos Farmakis, Christoforos Kosmidis.
      A significant factor in the antitumor immune response is the increased metabolic reprogramming of immunological and malignant cells. Increasing data points to the fact that cancer metabolism affects not just cancer signaling, which is essential for maintaining carcinogenesis and survival, but also the expression of immune cells and immune-related factors such as lactate, PGE2, arginine, IDO, which regulate the antitumor immune signaling mechanism. In reality, this energetic interaction between the immune system and the tumor results in metabolic competition in the tumor ecosystem, limiting the amount of nutrients available and causing microenvironmental acidosis, which impairs the ability of immune cells to operate. More intriguingly, different types of immune cells use metabolic reprogramming to keep the body and self in a state of homeostasis. The process of immune cell proliferation, differentiation, and performance of effector functions, which is crucial to the immune response, are currently being linked to metabolic reprogramming. Here, we cover the regulation of the antitumor immune response by metabolic reprogramming in cancer cells and immune cells as well as potential strategies for metabolic pathway targeting in the context of anticancer immunotherapy. We also discuss prospective immunotherapy-metabolic intervention combinations that might be utilized to maximize the effectiveness of current immunotherapy regimes.
    Keywords:  hypoxia; immunosuppression; metastasis; reprogramming; tumor metabolism
    DOI:  https://doi.org/10.3389/fimmu.2023.1325360
  3. J Hematol Oncol. 2024 Jan 31. 17(1): 6
    Metabolic reprogramming in the tumor microenvironment of liver cancer.
    Jian Lin, Dongning Rao, Mao Zhang, Qiang Gao.
      The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.
    Keywords:  Gut–liver axis; Immune microenvironment; Liver cancer; Metabolic reprogramming
    DOI:  https://doi.org/10.1186/s13045-024-01527-8
  4. Nat Cancer. 2024 Jan 29.
    Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma.
    Mahnoor Mahmood, Eric Minwei Liu, Amy L Shergold, Elisabetta Tolla, Jacqueline Tait-Mulder, Alejandro Huerta-Uribe, Engy Shokry, Alex L Young, Sergio Lilla, Minsoo Kim, Tricia Park, Sonia Boscenco, Javier L Manchon, Crístina Rodríguez-Antona, Rowan C Walters, Roger J Springett, James N Blaza, Louise Mitchell, Karen Blyth, Sara Zanivan, David Sumpton, Edward W Roberts, Ed Reznik, Payam A Gammage.
      The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.
    DOI:  https://doi.org/10.1038/s43018-023-00721-w
  5. Cell Rep Med. 2024 Jan 25. pii: S2666-3791(24)00006-5. [Epub ahead of print] 101397
    Multimodal immune phenotyping reveals microbial-T cell interactions that shape pancreatic cancer.
    Yan Li, Renee B Chang, Meredith L Stone, Devora Delman, Kelly Markowitz, Yuqing Xue, Heather Coho, Veronica M Herrera, Joey H Li, Liti Zhang, Shaanti Choi-Bose, Michael Giannone, Sarah M Shin, Erin M Coyne, Alexei Hernandez, Nicole E Gross, Soren Charmsaz, Won Jin Ho, Jae W Lee, Gregory L Beatty.
      Microbes are an integral component of the tumor microenvironment. However, determinants of microbial presence remain ill-defined. Here, using spatial-profiling technologies, we show that bacterial and immune cell heterogeneity are spatially coupled. Mouse models of pancreatic cancer recapitulate the immune-microbial spatial coupling seen in humans. Distinct intra-tumoral niches are defined by T cells, with T cell-enriched and T cell-poor regions displaying unique bacterial communities that are associated with immunologically active and quiescent phenotypes, respectively, but are independent of the gut microbiome. Depletion of intra-tumoral bacteria slows tumor growth in T cell-poor tumors and alters the phenotype and presence of myeloid and B cells in T cell-enriched tumors but does not affect T cell infiltration. In contrast, T cell depletion disrupts the immunological state of tumors and reduces intra-tumoral bacteria. Our results establish a coupling between microbes and T cells in cancer wherein spatially defined immune-microbial communities differentially influence tumor biology.
    Keywords:  T cells; bacteria; cellular communities; gut microbiome; immune system; lung adenocarcinoma; pancreatic ductal adenocarcinoma; spatial heterogeneity; tumor microbiome; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101397
  6. Lipids Health Dis. 2024 Feb 01. 23(1): 35
    Reprogramming of lipid metabolism in the tumor microenvironment: a strategy for tumor immunotherapy.
    Yuting Wu, Xi Pu, Xu Wang, Min Xu.
      Lipid metabolism in cancer cells has garnered increasing attention in recent decades. Cancer cells thrive in hypoxic conditions, nutrient deficiency, and oxidative stress and cannot be separated from alterations in lipid metabolism. Therefore, cancer cells exhibit increased lipid metabolism, lipid uptake, lipogenesis and storage to adapt to a progressively challenging environment, which contribute to their rapid growth. Lipids aid cancer cell activation. Cancer cells absorb lipids with the help of transporter and translocase proteins to obtain energy. Abnormal levels of a series of lipid synthases contribute to the over-accumulation of lipids in the tumor microenvironment (TME). Lipid reprogramming plays an essential role in the TME. Lipids are closely linked to several immune cells and their phenotypic transformation. The reprogramming of tumor lipid metabolism further promotes immunosuppression, which leads to immune escape. This event significantly affects the progression, treatment, recurrence, and metastasis of cancer. Therefore, the present review describes alterations in the lipid metabolism of immune cells in the TME and examines the connection between lipid metabolism and immunotherapy.
    Keywords:  Immunotherapy; Lipid metabolism; Programmed cell death protein 1; Targeted therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12944-024-02024-0
  7. Nat Commun. 2024 Feb 01. 15(1): 966
    Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.
    Rui Sun, Chao Lei, Zhishan Xu, Xuemei Gu, Liu Huang, Liang Chen, Yi Tan, Min Peng, Kavitha Yaddanapudi, Leah Siskind, Maiying Kong, Robert Mitchell, Jun Yan, Zhongbin Deng.
      The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.
    DOI:  https://doi.org/10.1038/s41467-024-45084-7
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