bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022–11–20
eight papers selected by
Linda Chan, Yale University
  1. Immunometabolism in the tumor microenvironment and its related research progress.
  2. OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment.
  3. Running to Outcompete Metastasis.
  4. The NLRP3 inflammasome: regulation by metabolic signals.
  5. Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth.
  6. Revealing de novo pyrimidine synthesis as a key vulnerability in brain tumors.
  7. Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer.
  8. Cancer cell survival depends on collagen uptake into tumor-associated stroma.
  1. Front Oncol. 2022 ;12 1024789
    Immunometabolism in the tumor microenvironment and its related research progress.
    Ziheng Zhang, Yajun Hu, Yuefeng Chen, Zhuoneng Chen, Yexin Zhu, Mingmin Chen, Jichu Xia, Yixuan Sun, Wenfang Xu.
      The tumor immune microenvironment has been a research hot spot in recent years. The cytokines and metabolites in the microenvironment can promote the occurrence and development of tumor in various ways and help tumor cells get rid of the surveillance of the immune system and complete immune escape. Many studies have shown that the existence of tumor microenvironment is an important reason for the failure of immunotherapy. The impact of the tumor microenvironment on tumor is a systematic study. The current research on this aspect may be only the tip of the iceberg, and a relative lack of integrity, may be related to the heterogeneity of tumor. This review mainly discusses the current status of glucose metabolism and lipid metabolism in the tumor microenvironment, including the phenotype of glucose metabolism and lipid metabolism in the microenvironment; the effects of these metabolic methods and their metabolites on three important immune cells Impact: regulatory T cells (Tregs), tumor-associated macrophages (TAM), natural killer cells (NK cells); and the impact of metabolism in the targeted microenvironment on immunotherapy. At the end of this article,the potential relationship between Ferroptosis and the tumor microenvironment in recent years is also briefly described.
    Keywords:  NK cells; Tregs; glucose metabolism; lipid metabolism; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1024789
  2. Sci Immunol. 2022 Nov 25. 7(77): eabm8182
    OXPHOS promotes apoptotic resistance and cellular persistence in TH17 cells in the periphery and tumor microenvironment.
    Hanna S Hong, Nneka E Mbah, Mengrou Shan, Kristen Loesel, Lin Lin, Peter Sajjakulnukit, Luis O Correa, Anthony Andren, Jason Lin, Atsushi Hayashi, Brian Magnuson, Judy Chen, Zhaoheng Li, Yuying Xie, Li Zhang, Daniel R Goldstein, Shannon A Carty, Yu Leo Lei, Anthony W Opipari, Rafael J Argüello, Ilona Kryczek, Nobuhiko Kamada, Weiping Zou, Luigi Franchi, Costas A Lyssiotis.
      T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17-producing CD4 T cells (TH17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. TH17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that TH17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates TH17 processes, such as their ability to persist and thus contribute to protracted immune responses. Here, we modified standardized culture medium and identified a culture system that reliably induces OXPHOS dependence in TH17s. We found that TH17s cultured under OXPHOS conditions metabolically resembled their in vivo counterparts, whereas glycolytic cultures were dissimilar. OXPHOS TH17s exhibited increased mitochondrial fitness, glutamine anaplerosis, and an antiapoptotic phenotype marked by high BCL-XL and low BIM. Limited mitophagy, mediated by mitochondrial fusion regulator OPA-1, was critical to apoptotic resistance in OXPHOS TH17s. By contrast, glycolytic TH17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. In addition, through adoptive transfer experiments, we demonstrated that OXPHOS protected TH17s from apoptosis while enhancing their persistence in the periphery and tumor microenvironment in a murine model of melanoma. Together, our work demonstrates how metabolism regulates TH17 cell fate and highlights the potential for therapies that target OXPHOS in TH17-driven diseases.
    DOI:  https://doi.org/10.1126/sciimmunol.abm8182
  3. Cancer Res. 2022 Nov 15. 82(22): 4124-4125
    Running to Outcompete Metastasis.
    Marwa Zerhouni, Elena Piskounova.
      The role of exercise in cancer progression is an emerging field of research, with intriguing evidence for physical activity playing an inhibitory role in cancer onset. In their recent publication, Sheinboim and colleagues demonstrate the impact of physical exercise on melanoma primary tumor growth and metastasis. They establish that physical exercise decreases metastatic spread, using both human epidemiologic data and in vivo models of melanoma metastasis. Systemic metabolic reprogramming of organs, induced by exercise, leads to a decrease in melanoma growth and progression as healthy organs are able to outcompete melanoma cells for nutrients. Exercise led to systemic metabolic changes in carbohydrate metabolism, glycolysis, and oxidative phosphorylation as well as mitochondrial biogenesis. Interestingly, the "metabolic shield" created by exercise could be reversed using the mTOR inhibitor rapamycin. This study highlights the importance of metabolic plasticity in metastasis and uncovers a direct link between systemic metabolic reprogramming and mTOR signaling. Overall, the study by Sheinboim and colleagues provides a more detailed understanding of the metastatic requirements in the context of energy and nutrient availability and the impact of exercise on cancer progression, highlighting novel opportunities for therapeutic intervention. See related article by Sheinboim et al., p. 4164.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2898
  4. Trends Immunol. 2022 Nov 09. pii: S1471-4906(22)00211-3. [Epub ahead of print]
    The NLRP3 inflammasome: regulation by metabolic signals.
    Antoni Olona, Stuart Leishman, Paras K Anand.
      Macrophages undergo profound metabolic reprogramming upon sensing infectious and sterile stimuli. This metabolic shift supports and regulates essential innate immune functions, including activation of the NLRP3 inflammasome. Within distinct metabolic networks, key enzymes play pivotal roles to control flux restraining detrimental inflammasome signaling. However, depending on the metabolic cues, specific enzymes and metabolites result in inflammasome activation outcomes which contrast other metabolic steps in the pathway. We posit that understanding which metabolic steps commit to discrete inflammasome fates will broaden our understanding of metabolic checkpoints to maintain homeostasis and offer better therapeutic options in human disease.
    Keywords:  NLRP3; TCA cycle; glycolysis; inflammasome; lipids; metabolism
    DOI:  https://doi.org/10.1016/j.it.2022.10.003
  5. Nat Metab. 2022 Nov 14.
    Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth.
    Hongyun Zhao, Da Teng, Lifeng Yang, Xincheng Xu, Jiajia Chen, Tengjia Jiang, Austin Y Feng, Yaqing Zhang, Dennie T Frederick, Lei Gu, Li Cai, John M Asara, Marina Pasca di Magliano, Genevieve M Boland, Keith T Flaherty, Kenneth D Swanson, David Liu, Joshua D Rabinowitz, Bin Zheng.
      The tumour microenvironment possesses mechanisms that suppress anti-tumour immunity. Itaconate is a metabolite produced from the Krebs cycle intermediate cis-aconitate by the activity of immune-responsive gene 1 (IRG1). While it is known to be immune modulatory, the role of itaconate in anti-tumour immunity is unclear. Here, we demonstrate that myeloid-derived suppressor cells (MDSCs) secrete itaconate that can be taken up by CD8+ T cells and suppress their proliferation, cytokine production and cytolytic activity. Metabolite profiling, stable-isotope tracing and metabolite supplementation studies indicated that itaconate suppressed the biosynthesis of aspartate and serine/glycine in CD8+ T cells to attenuate their proliferation and function. Host deletion of Irg1 in female mice bearing allografted tumours resulted in decreased tumour growth, inhibited the immune-suppressive activities of MDSCs, promoted anti-tumour immunity of CD8+ T cells and enhanced the anti-tumour activity of anti-PD-1 antibody treatment. Furthermore, we found a significant negative correlation between IRG1 expression and response to PD-1 immune checkpoint blockade in patients with melanoma. Our findings not only reveal a previously unknown role of itaconate as an immune checkpoint metabolite secreted from MDSCs to suppress CD8+ T cells, but also establish IRG1 as a myeloid-selective target in immunometabolism whose inhibition promotes anti-tumour immunity and enhances the efficacy of immune checkpoint protein blockade.
    DOI:  https://doi.org/10.1038/s42255-022-00676-9
  6. Cancer Cell. 2022 Nov 09. pii: S1535-6108(22)00520-7. [Epub ahead of print]
    Revealing de novo pyrimidine synthesis as a key vulnerability in brain tumors.
    Tanya Schild, Kayvan R Keshari.
      Brain tumors are notoriously difficult to treat. Three recent Cancer Cell articles aim to uncover novel druggable targets in IDH mutant gliomas, diffuse midline gliomas, and medulloblastomas, respectively, and show that these brain tumor types shift their metabolism to become reliant on de novo pyrimidine synthesis.
    DOI:  https://doi.org/10.1016/j.ccell.2022.10.023
  7. Sci Adv. 2022 Nov 18. 8(46): eabq0615
    Chronic exposure to carbon black ultrafine particles reprograms macrophage metabolism and accelerates lung cancer.
    Cheng-Yen Chang, Ran You, Dominique Armstrong, Ashwini Bandi, Yi-Ting Cheng, Philip M Burkhardt, Luis Becerra-Dominguez, Matthew C Madison, Hui-Ying Tung, Zhimin Zeng, Yifan Wu, Lizhen Song, Patricia E Phillips, Paul Porter, John M Knight, Nagireddy Putluri, Xiaoyi Yuan, Daniela C Marcano, Emily A McHugh, James M Tour, Andre Catic, Laure Maneix, Bryan M Burt, Hyun-Sung Lee, David B Corry, Farrah Kheradmand.
      Chronic exposure to airborne carbon black ultrafine (nCB) particles generated from incomplete combustion of organic matter drives IL-17A-dependent emphysema. However, whether and how they alter the immune responses to lung cancer remains unknown. Here, we show that exposure to nCB particles increased PD-L1+ PD-L2+ CD206+ antigen-presenting cells (APCs), exhausted T cells, and Treg cells. Lung macrophages that harbored nCB particles showed selective mitochondrial structure damage and decreased oxidative respiration. Lung macrophages sustained the HIF1α axis that increased glycolysis and lactate production, culminating in an immunosuppressive microenvironment in multiple mouse models of non-small cell lung cancers. Adoptive transfer of lung APCs from nCB-exposed wild type to susceptible mice increased tumor incidence and caused early metastasis. Our findings show that nCB exposure metabolically rewires lung macrophages to promote immunosuppression and accelerates the development of lung cancer.
    DOI:  https://doi.org/10.1126/sciadv.abq0615
  8. Nat Commun. 2022 Nov 18. 13(1): 7078
    Cancer cell survival depends on collagen uptake into tumor-associated stroma.
    Kuo-Sheng Hsu, James M Dunleavey, Christopher Szot, Liping Yang, Mary Beth Hilton, Karen Morris, Steven Seaman, Yang Feng, Emily M Lutz, Robert Koogle, Francesco Tomassoni-Ardori, Saurabh Saha, Xiaoyan M Zhang, Enrique Zudaire, Pradip Bajgain, Joshua Rose, Zhongyu Zhu, Dimiter S Dimitrov, Frank Cuttitta, Nancy J Emenaker, Lino Tessarollo, Brad St Croix.
      Collagen I, the most abundant protein in humans, is ubiquitous in solid tumors where it provides a rich source of exploitable metabolic fuel for cancer cells. While tumor cells were unable to exploit collagen directly, here we show they can usurp metabolic byproducts of collagen-consuming tumor-associated stroma. Using genetically engineered mouse models, we discovered that solid tumor growth depends upon collagen binding and uptake mediated by the TEM8/ANTXR1 cell surface protein in tumor-associated stroma. Tumor-associated stromal cells processed collagen into glutamine, which was then released and internalized by cancer cells. Under chronic nutrient starvation, a condition driven by the high metabolic demand of tumors, cancer cells exploited glutamine to survive, an effect that could be reversed by blocking collagen uptake with TEM8 neutralizing antibodies. These studies reveal that cancer cells exploit collagen-consuming stromal cells for survival, exposing an important vulnerability across solid tumors with implications for developing improved anticancer therapy.
    DOI:  https://doi.org/10.1038/s41467-022-34643-5
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