bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–03–03
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Metabolic rewiring and communication in cancer immunity.
  2. Advances in reprogramming of energy metabolism in tumor T cells.
  3. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
  4. Metabolic Landscape of Osteosarcoma: Reprogramming of Lactic Acid Metabolism and Metabolic Communication.
  5. From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.
  6. Lymphatic endothelial-like cells in the glioblastoma tumor niche drive metabolic alterations that promote stem cell proliferation and survival.
  7. Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.
  8. IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
  9. Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.
  10. Arginase-1 specific CD8+ T cells react toward malignant and regulatory myeloid cells.
  11. Hypoxia-related carbonic anhydrase 9 induces serpinB9 expression in cancer cells and apoptosis in T cells via acidosis.
  1. Cell Chem Biol. 2024 Feb 26. pii: S2451-9456(24)00075-8. [Epub ahead of print]
    Metabolic rewiring and communication in cancer immunity.
    Nicole M Chapman, Hongbo Chi.
      The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.02.001
  2. Front Immunol. 2024 ;15 1347181
    Advances in reprogramming of energy metabolism in tumor T cells.
    Liu Xuekai, Song Yan, Chu Jian, Song Yifei, Wu Xinyue, Zhang Wenyuan, Han Shuwen, Yang Xi.
      Cancer is a leading cause of human death worldwide, and the modulation of the metabolic properties of T cells employed in cancer immunotherapy holds great promise for combating cancer. As a crucial factor, energy metabolism influences the activation, proliferation, and function of T cells, and thus metabolic reprogramming of T cells is a unique research perspective in cancer immunology. Special conditions within the tumor microenvironment and high-energy demands lead to alterations in the energy metabolism of T cells. In-depth research on the reprogramming of energy metabolism in T cells can reveal the mechanisms underlying tumor immune tolerance and provide important clues for the development of new tumor immunotherapy strategies as well. Therefore, the study of T cell energy metabolism has important clinical significance and potential applications. In the study, the current achievements in the reprogramming of T cell energy metabolism were reviewed. Then, the influencing factors associated with T cell energy metabolism were introduced. In addition, T cell energy metabolism in cancer immunotherapy was summarized, which highlighted its potential significance in enhancing T cell function and therapeutic outcomes. In summary, energy exhaustion of T cells leads to functional exhaustion, thus resulting in immune evasion by cancer cells. A better understanding of reprogramming of T cell energy metabolism may enable immunotherapy to combat cancer and holds promise for optimizing and enhancing existing therapeutic approaches.
    Keywords:  T cells; energy metabolism; immune microenvironment; immunotherapy; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2024.1347181
  3. Nat Cell Biol. 2024 Mar 01.
    Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
    Divya Murthy, Kuldeep S Attri, Surendra K Shukla, Ravi Thakur, Nina V Chaika, Chunbo He, Dezhen Wang, Kanupriya Jha, Aneesha Dasgupta, Ryan J King, Scott E Mulder, Joshua Souchek, Teklab Gebregiworgis, Vikant Rai, Rohit Patel, Tuo Hu, Sandeep Rana, Sai Sundeep Kollala, Camila Pacheco, Paul M Grandgenett, Fang Yu, Vikas Kumar, Audrey J Lazenby, Adrian R Black, Susanna Ulhannan, Ajay Jain, Barish H Edil, David L Klinkebiel, Robert Powers, Amarnath Natarajan, Michael A Hollingsworth, Kamiya Mehla, Quan Ly, Sarika Chaudhary, Rosa F Hwang, Kathryn E Wellen, Pankaj K Singh.
      The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
    DOI:  https://doi.org/10.1038/s41556-024-01372-4
  4. Front Biosci (Landmark Ed). 2024 Feb 22. 29(2): 83
    Metabolic Landscape of Osteosarcoma: Reprogramming of Lactic Acid Metabolism and Metabolic Communication.
    Linbang Wang, Xinyu Dou, Linzhen Xie, Xuchang Zhou, Yu Liu, Jingkun Liu, Xiaoguang Liu.
       BACKGROUND: Lactic acid, previously regarded only as an endpoint of glycolysis, has emerged as a major regulator of tumor invasion, growth, and the tumor microenvironment. In this study, we aimed to explore the reprogramming of lactic acid metabolism relevant to osteosarcoma (OS) microenvironment by decoding the underlying lactic acid metabolic landscape of OS cells and intercellular signaling alterations.
    METHODS: The landscape of OS metabolism was evaluated using single-cell gene expression data, lactic acid metabolism clustering, and screening of the hub genes in lactic acid metabolism of OS samples using transcriptome data. The role of the hub gene NADH:Ubiquinone Oxidoreductase Complex Assembly Factor 6 (NDUFAF6) was validated with in vitro studies and patient experiments.
    RESULTS: Single-cell RNA sequencing data validated a lactic acid metabolismhigh subcluster in OS. Further investigation of intercellular communications revealed a unique metabolic communication pattern between the lactic acid metabolismhigh subcluster and other subclusters. Next, two lactic acid metabolic reprogramming phenotypes were defined, and six lactic acid metabolism-related genes (LRGs), including the biomarker NDUFAF6, were screened in OS. In vitro studies and patient experiments confirmed that NDUFAF6 is a crucial lactic acid metabolism-associated gene in OS.
    CONCLUSIONS: The patterns of lactic acid metabolism in OS suggested metabolic reprogramming phenotypes relevant to the tumor microenvironment (TME) and identified NDUFAF6 as an LRG prognostic biomarker.
    Keywords:  NDUFAF6; lactic acid metabolism; metabolic communication; metabolic reprogramming; osteosarcoma
    DOI:  https://doi.org/10.31083/j.fbl2902083
  5. Mol Oncol. 2024 Feb 27.
    From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.
    Ummi Ammarah, Andreia Pereira-Nunes, Marcello Delfini, Massimiliano Mazzone.
      Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor-associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche-derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype-specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.
    Keywords:  cancer metabolism; immunometabolism; monocyte-derived macrophages; tissue-resident macrophages; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1002/1878-0261.13618
  6. Neuro Oncol. 2024 Feb 28. pii: noae020. [Epub ahead of print]
    Lymphatic endothelial-like cells in the glioblastoma tumor niche drive metabolic alterations that promote stem cell proliferation and survival.
    Reilly L Kidwell, Manish K Aghi.
      
    DOI:  https://doi.org/10.1093/neuonc/noae020
  7. bioRxiv. 2024 Feb 16. pii: 2024.02.14.580339. [Epub ahead of print]
    Circadian rhythms of macrophages are altered by the acidic pH of the tumor microenvironment.
    Amelia M Knudsen-Clark, Daniel Mwangi, Juliana Cazarin, Lauren M Hablitz, Minsoo Kim, Brian J Altman.
      Macrophages are prime therapeutic targets due to their pro-tumorigenic and immunosuppressive functions in tumors, but varying efficacy of therapeutic approaches targeting macrophages highlights our incomplete understanding of how the tumor microenvironment (TME) can influence regulation of macrophages. The circadian clock is a key internal regulator of macrophage function, but how circadian rhythms of macrophages may be influenced by the tumor microenvironment remains unknown. We found that conditions associated with the TME such as polarizing stimuli, acidic pH, and elevated lactate concentrations can each alter circadian rhythms in macrophages. Circadian rhythms were enhanced in pro-resolution macrophages but suppressed in pro-inflammatory macrophages, while acidic pH had divergent effects on circadian rhythms depending on macrophage phenotype. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate that pH-driven changes in circadian rhythms are not mediated solely by the cAMP signaling pathway. Remarkably, clock correlation distance analysis of tumor-associated macrophages (TAMs) revealed evidence of circadian disorder in TAMs. This is the first report providing evidence that circadian rhythms of macrophages are altered within the TME. Our data suggest that heterogeneity in circadian rhythms at the population level may underlie this circadian disorder. Finally, we sought to determine how circadian regulation of macrophages impacts tumorigenesis, and found that tumor growth was suppressed when macrophages had a functional circadian clock. Our work demonstrates a novel mechanism by which the tumor microenvironment can influence macrophage biology through altering circadian rhythms, and the contribution of circadian rhythms in macrophages to suppressing tumor growth.
    DOI:  https://doi.org/10.1101/2024.02.14.580339
  8. Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00163-3. [Epub ahead of print]43(3): 113835
    IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
    Yu Mei, Ying Zhu, Kylie Su Mei Yong, Zuhairah Binte Hanafi, Huanle Gong, Yonghao Liu, Huey Yee Teo, Muslima Hussain, Yuan Song, Qingfeng Chen, Haiyan Liu.
      Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.
    Keywords:  ATP; CP: Cancer; CP: Immunology; Interleukin-37; hepatocellular carcinoma; metabolism; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1016/j.celrep.2024.113835
  9. Immunity. 2024 Feb 15. pii: S1074-7613(24)00045-1. [Epub ahead of print]
    Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells.
    Rui Ding, Xiaoyan Yu, Zhilin Hu, Yu Dong, Haiyan Huang, Yuerong Zhang, Qiaoqiao Han, Zhi-Yu Ni, Ren Zhao, Youqiong Ye, Qiang Zou.
      RNA splicing is involved in cancer initiation and progression, but how it influences host antitumor immunity in the metabolically abnormal tumor microenvironment (TME) remains unclear. Here, we demonstrate that lactate modulates Foxp3-dependent RNA splicing to maintain the phenotypic and functional status of tumor-infiltrating regulatory T (Treg) cells via CTLA-4. RNA splicing in Treg cells was correlated with the Treg cell signatures in the TME. Ubiquitin-specific peptidase 39 (USP39), a component of the RNA splicing machinery, maintained RNA-splicing-mediated CTLA-4 expression to control Treg cell function. Mechanistically, lactate promoted USP39-mediated RNA splicing to facilitate CTLA-4 expression in a Foxp3-dependent manner. Moreover, the efficiency of CTLA-4 RNA splicing was increased in tumor-infiltrating Treg cells from patients with colorectal cancer. These findings highlight the immunological relevance of RNA splicing in Treg cells and provide important insights into the environmental mechanism governing CTLA-4 expression in Treg cells.
    Keywords:  CTLA-4; RNA splicing; Treg cells; lactate
    DOI:  https://doi.org/10.1016/j.immuni.2024.01.019
  10. Oncoimmunology. 2024 ;13(1): 2318053
    Arginase-1 specific CD8+ T cells react toward malignant and regulatory myeloid cells.
    Hannah Jorinde Glöckner, Evelina Martinenaite, Thomas Landkildehus Lisle, Jacob Grauslund, Shamaila Ahmad, Özcan Met, Per Thor Straten, Mads Hald Andersen.
      Arginase-1 (Arg1) is expressed by regulatory myeloid cells in the tumor microenvironment (TME), where they play a pro-tumorigenic and T-cell suppressive role. Arg1-specific CD4+ and CD8+ memory T cells have been observed in both healthy individuals and cancer patients. However, while the function of anti-regulatory Arg1-specific CD4+ T cells has been characterized, our knowledge of CD8+ Arg1-specific T cells is only scarce. In the current study, we describe the immune-modulatory capabilities of CD8+ Arg1-specific T cells. We generated CD8+ Arg1-specific T cell clones to target Arg1-expressing myeloid cells. Our results demonstrate that these T cells recognize both malignant and nonmalignant regulatory myeloid cells in an Arg1-expression-dependent manner. Notably, Arg1-specific CD8+ T cells possess cytolytic effector capabilities. Immune modulatory vaccines (IMVs) represent a novel treatment modality for cancer. The activation of Arg1-specific CD8+ T cells through Arg1-based IMVs can contribute to the modulatory effects of this treatment strategy.
    Keywords:  Arginase-1; anti-regulatory T cells; immune modulatory vaccines; myeloid cells; tumor microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2024.2318053
  11. Cancer Sci. 2024 Feb 27.
    Hypoxia-related carbonic anhydrase 9 induces serpinB9 expression in cancer cells and apoptosis in T cells via acidosis.
    Mamoru Harada, Hitoshi Kotani, Yuichi Iida, Ryosuke Tanino, Takafumi Minami, Yoshihiro Komohara, Kazuhiro Yoshikawa, Hirotsugu Uemura.
      Hypoxia is a common feature of solid tumors. However, the impact of hypoxia on immune cells within tumor environments remains underexplored. Carbonic anhydrase 9 (CA9) is a hypoxia-responsive tumor-associated enzyme. We previously noted that regardless of human CA9 (hCA9) expression, hCA9-expressing mouse renal cell carcinoma RENCA (RENCA/hCA9) presented as a "cold" tumor in syngeneic aged mice. This study delves into the mechanisms behind this observation. Gene microarray analyses showed that RENCA/hCA9 cells exhibited elevated mouse serpinB9, an inhibitor of granzyme B, relative to RENCA cells. Corroborating this, RENCA/hCA9 cells displayed heightened resistance to antigen-specific cytotoxic T cells compared with RENCA cells. Notably, siRNA-mediated serpinB9 knockdown reclaimed this sensitivity. In vivo tests showed that serpinB9 inhibitor administration slowed RENCA tumor growth, but this effect was reduced in RENCA/hCA9 tumors, even with adjunctive immune checkpoint blockade therapy. Further, inducing hypoxia or introducing the mouse CA9 gene upregulated serpinB9 expression, and siRNA-mediated knockdown of the mouse CA9 gene inhibited the hypoxia-induced induction of serpinB9 in the original RENCA cells. Supernatants from RENCA/hCA9 cultures had lower pH than those from RENCA, suggesting acidosis. This acidity enhanced serpinB9 expression and T cell apoptosis. Moreover, coculturing with RENCA/hCA9 cells more actively prompted T cell apoptosis than with RENCA cells. Collectively, these findings suggest hypoxia-associated CA9 not only boosts serpinB9 in cancer cells but also synergistically intensifies T cell apoptosis via acidosis, characterizing RENCA/hCA9 tumors as "cold."
    Keywords:  acidosis; carbonic anhydrase 9; hypoxia; serpin B9
    DOI:  https://doi.org/10.1111/cas.16133
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