bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–09–24
nineteen papers selected by
Oltea Sampetrean, Keio University
  1. Glutamine availability unleashes dendritic cells' anti-tumor power.
  2. Functional polarization of tumor-associated macrophages dictated by metabolic reprogramming.
  3. Dietary fat and lipid metabolism in the tumor microenvironment.
  4. Reductive carboxylation epigenetically instructs T cell differentiation.
  5. Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
  6. Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.
  7. Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer.
  8. Understanding metabolic reprogramming in tumor microenvironment.
  9. Immunometabolism: a new dimension in immunotherapy resistance.
  10. Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
  11. Metabolic diversity of tumor-infiltrating T cells as target for anti-immune therapeutics.
  12. Extracellular vesicles in cancer: Shaping the intricate network of metabolic reprogramming and immune interactions in the tumor microenvironment.
  13. Manipulating mitochondrial electron flow enhances tumor immunogenicity.
  14. The dual role of citrate in cancer.
  15. Targeting the NAD+ Salvage Pathway: Synergistic Therapeutic Strategy for ER+ Metastatic Breast Cancer.
  16. Spermidine - an old molecule with a new age-defying immune function.
  17. Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer.
  18. PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.
  19. Metabolic control of antitumor immunity.
  1. Cell Chem Biol. 2023 Sep 21. pii: S2451-9456(23)00284-2. [Epub ahead of print]30(9): 1012-1014
    Glutamine availability unleashes dendritic cells' anti-tumor power.
    Mauro Corrado, Christian Frezza.
      Metabolic competition within the tumor microenvironment (TME) shapes the efficacy of anticancer immunity. In the August 3rd issue of Nature, Guo et al.1 show that glutamine is an intercellular metabolic checkpoint between cancer and immune cells. Targeting glutamine metabolism in the TME is a promising strategy to improve anti-cancer therapy.
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.012
  2. J Exp Clin Cancer Res. 2023 Sep 23. 42(1): 245
    Functional polarization of tumor-associated macrophages dictated by metabolic reprogramming.
    Wentao Zeng, Fei Li, Shikai Jin, Ping-Chih Ho, Pu-Ste Liu, Xin Xie.
      Macrophages are highly plastic in different tissues and can differentiate into functional subpopulations under different stimuli. Tumor-associated macrophages (TAMs) are one of the most important innate immune cells implicated in the establishment of an immunosuppressive tumor microenvironment (TME). Recent evidence pinpoints the critical role of metabolic reprogramming in dictating pro-tumorigenic functions of TAMs. Both tumor cells and macrophages undergo metabolic reprogramming to meet energy demands in the TME. Understanding the metabolic rewiring in TAMs can shed light on immune escape mechanisms and provide insights into repolarizing TAMs towards anti-tumorigenic function. Here, we discuss how metabolism impinges on the functional divergence of macrophages and its relevance to macrophage polarization in the TME.
    Keywords:  Metabolic reprogramming; Polarization; Signaling pathways; TAMs; TME
    DOI:  https://doi.org/10.1186/s13046-023-02832-9
  3. Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984
    Dietary fat and lipid metabolism in the tumor microenvironment.
    Swagata Goswami, Qiming Zhang, Cigdem Elif Celik, Ethan M Reich, Ömer H Yilmaz.
      Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.
    Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188984
  4. Nature. 2023 Sep 20.
    Reductive carboxylation epigenetically instructs T cell differentiation.
    Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Jan A Rath, Alessio Bevilacqua, Jhan-Jie Peng, Anouk Lepez, Christine Von Gunten, Fabien Franco, Kung-Chi Kao, Nicolas Camviel, Francisco Martín, Bart Ghesquière, Denis Migliorini, Caroline Arber, Pedro Romero, Ping-Chih Ho, Mathias Wenes.
      Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+ T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.
    DOI:  https://doi.org/10.1038/s41586-023-06546-y
  5. Cancer Discov. 2023 Sep 20.
    Formate supplementation enhances anti-tumor CD8+ T cell fitness and efficacy of PD-1 blockade.
    Jared H Rowe, Ilaria Elia, Osmaan Shahid, Emily F Gaudiano, Natalia E Sifnugel, Sheila Johnson, Amy G Reynolds, Megan E Fung, Shakchhi Joshi, Martin W LaFleur, Joon Seok Park, Kristen E Pauken, Joshua D Rabinowitz, Gordon J Freeman, Marcia C Haigis, Arlene H Sharpe.
      The tumor microenvironment (TME) restricts anti-tumor CD8+ T cell function and immunotherapy responses. Cancer cells compromise metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate one carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T cell fitness and anti-tumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti-PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for the enhanced tumor control. Our data demonstrate formate provides metabolic support to CD8+ T cells reinvigorated by anti-PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T cell function.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1301
  6. Sci Immunol. 2023 Sep 29. 8(87): eadf7579
    Regulatory circuits of mitophagy restrict distinct modes of cell death during memory CD8+ T cell formation.
    Fabien Franco, Alessio Bevilacqua, Ruey-Mei Wu, Kung-Chi Kao, Chun-Pu Lin, Lorène Rousseau, Fu-Ti Peng, Yu-Ming Chuang, Jhan-Jie Peng, Jaeoh Park, Yingxi Xu, Antonino Cassotta, Yi-Ru Yu, Daniel E Speiser, Federica Sallusto, Ping-Chih Ho.
      Mitophagy, a central process guarding mitochondrial quality, is commonly impaired in human diseases such as Parkinson's disease, but its impact in adaptive immunity remains unclear. The differentiation and survival of memory CD8+ T cells rely on oxidative metabolism, a process that requires robust mitochondrial quality control. Here, we found that Parkinson's disease patients have a reduced frequency of CD8+ memory T cells compared with healthy donors and failed to form memory T cells upon vaccination against COVID-19, highlighting the importance of mitochondrial quality control for memory CD8+ T cell formation. We further uncovered that regulators of mitophagy, including Parkin and NIX, were up-regulated in response to interleukin-15 (IL-15) for supporting memory T cell formation. Mechanistically, Parkin suppressed VDAC1-dependent apoptosis in memory T cells. In contrast, NIX expression in T cells counteracted ferroptosis by preventing metabolic dysfunction resulting from impaired mitophagy. Together, our results indicate that the mitophagy machinery orchestrates survival and metabolic dynamics required for memory T cell formation, as well as highlight a deficit in T cell-mediated antiviral responses in Parkinson's disease patients.
    DOI:  https://doi.org/10.1126/sciimmunol.adf7579
  7. Nat Cancer. 2023 Sep 18.
    Acetate acts as a metabolic immunomodulator by bolstering T-cell effector function and potentiating antitumor immunity in breast cancer.
    Katelyn D Miller, Seamus O'Connor, Katherine A Pniewski, Toshitha Kannan, Reyes Acosta, Gauri Mirji, Sara Papp, Michael Hulse, Dzmitry Mukha, Sabina I Hlavaty, Kelsey N Salcido, Fabrizio Bertolazzi, Yellamelli V V Srikanth, Steven Zhao, Kathryn E Wellen, Rahul S Shinde, Daniel T Claiborne, Andrew Kossenkov, Joseph M Salvino, Zachary T Schug.
      Acetate metabolism is an important metabolic pathway in many cancers and is controlled by acetyl-CoA synthetase 2 (ACSS2), an enzyme that catalyzes the conversion of acetate to acetyl-CoA. While the metabolic role of ACSS2 in cancer is well described, the consequences of blocking tumor acetate metabolism on the tumor microenvironment and antitumor immunity are unknown. We demonstrate that blocking ACSS2, switches cancer cells from acetate consumers to producers of acetate thereby freeing acetate for tumor-infiltrating lymphocytes to use as a fuel source. We show that acetate supplementation metabolically bolsters T-cell effector functions and proliferation. Targeting ACSS2 with CRISPR-Cas9 guides or a small-molecule inhibitor promotes an antitumor immune response and enhances the efficacy of chemotherapy in preclinical breast cancer models. We propose a paradigm for targeting acetate metabolism in cancer in which inhibition of ACSS2 dually acts to impair tumor cell metabolism and potentiate antitumor immunity.
    DOI:  https://doi.org/10.1038/s43018-023-00636-6
  8. Med Rev (Berl). 2021 Dec;1(2): 111-113
    Understanding metabolic reprogramming in tumor microenvironment.
    Shaokun Shu, Ying Xu, Qimin Zhan.
      
    DOI:  https://doi.org/10.1515/mr-2021-0037
  9. Front Med. 2023 Sep 19.
    Immunometabolism: a new dimension in immunotherapy resistance.
    Chaoyue Xiao, Wei Xiong, Yiting Xu, Ji'an Zou, Yue Zeng, Junqi Liu, Yurong Peng, Chunhong Hu, Fang Wu.
      Immune checkpoint inhibitors (ICIs) have demonstrated unparalleled clinical responses and revolutionized the paradigm of tumor treatment, while substantial patients remain unresponsive or develop resistance to ICIs as a single agent, which is traceable to cellular metabolic dysfunction. Although dysregulated metabolism has long been adjudged as a hallmark of tumor, it is now increasingly accepted that metabolic reprogramming is not exclusive to tumor cells but is also characteristic of immunocytes. Correspondingly, people used to pay more attention to the effect of tumor cell metabolism on immunocytes, but in practice immunocytes interact intimately with their own metabolic function in a way that has never been realized before during their activation and differentiation, which opens up a whole new frontier called immunometabolism. The metabolic intervention for tumor-infiltrating immunocytes could offer fresh opportunities to break the resistance and ameliorate existing ICI immunotherapy, whose crux might be to ascertain synergistic combinations of metabolic intervention with ICIs to reap synergic benefits and facilitate an adjusted anti-tumor immune response. Herein, we elaborate potential mechanisms underlying immunotherapy resistance from a novel dimension of metabolic reprogramming in diverse tumor-infiltrating immunocytes, and related metabolic intervention in the hope of offering a reference for targeting metabolic vulnerabilities to circumvent immunotherapeutic resistance.
    Keywords:  immune cell; immune checkpoint inhibitor; immunometabolism; immunotherapy; metabolic reprogramming; resistance; tumor microenvironment
    DOI:  https://doi.org/10.1007/s11684-023-1012-z
  10. Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00280-5. [Epub ahead of print]
    Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
    Kiran Kurmi, Dan Liang, Robert van de Ven, Peter Georgiev, Brandon Mark Gassaway, SeongJun Han, Giulia Notarangelo, Isaac S Harris, Cong-Hui Yao, Joon Seok Park, Song-Hua Hu, Jingyu Peng, Jefte M Drijvers, Sarah Boswell, Artem Sokolov, Stephanie K Dougan, Peter K Sorger, Steven P Gygi, Arlene H Sharpe, Marcia C Haigis.
      Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.
    Keywords:  CD4(+) T cells; T cell differentiation; high-throughput metabolic screen; mitochondrial biogenesis; pyruvate oxidation; pyrvinium pamoate
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.008
  11. Cancer Immunol Immunother. 2023 Sep 21.
    Metabolic diversity of tumor-infiltrating T cells as target for anti-immune therapeutics.
    Peipei Li, Fangchao Li, Yanfei Zhang, Xiaoyang Yu, Jingjing Li.
      Tumor-infiltrating T cells are promising drug targets to modulate the tumor microenvironment. However, tumor-infiltrating T lymphocytes, as central targets of cancer immunotherapy, show considerable heterogeneity and dynamics across tumor microenvironments and cancer types that may fundamentally influence cancer growth, metastasis, relapse, and response to clinical drugs. The T cell heterogeneity not only refers to the composition of subpopulations but also divergent metabolic states of T cells. Comparing to the diversity of tumor-infiltrating T cell compositions that have been well recognized, the metabolic diversity of T cells deserves more attention for precision immunotherapy. Single-cell sequencing technology enables panoramic stitching of the tumor bulk, partly by showing the metabolic-related gene expression profiles of tumor-infiltrating T cells at a single-cell resolution. Therefore, we here discuss T cell metabolism reprogramming triggered by tumor microenvironment as well as the potential application of metabolic targeting drugs. The tumor-infiltrating T cells metabolic pathway addictions among different cancer types are also addressed in this brief review.
    Keywords:  Cancer metabolism; Single-cell sequencing; T cell metabolism; Tumor microenvironment; Tumor-infiltrating T cell
    DOI:  https://doi.org/10.1007/s00262-023-03540-1
  12. Cytokine Growth Factor Rev. 2023 Sep 15. pii: S1359-6101(23)00063-1. [Epub ahead of print]
    Extracellular vesicles in cancer: Shaping the intricate network of metabolic reprogramming and immune interactions in the tumor microenvironment.
    Elisa Giovannetti, Tian Li.
      
    DOI:  https://doi.org/10.1016/j.cytogfr.2023.09.001
  13. Science. 2023 Sep 22. 381(6664): 1316-1323
    Manipulating mitochondrial electron flow enhances tumor immunogenicity.
    Kailash Chandra Mangalhara, Siva Karthik Varanasi, Melissa A Johnson, Mannix J Burns, Gladys R Rojas, Pau B Esparza Moltó, Alva G Sainz, Nimesha Tadepalle, Keene L Abbott, Gaurav Mendiratta, Dan Chen, Yagmur Farsakoglu, Tenzin Kunchok, Filipe Araujo Hoffmann, Bianca Parisi, Mercedes Rincon, Matthew G Vander Heiden, Marcus Bosenberg, Diana C Hargreaves, Susan M Kaech, Gerald S Shadel.
      Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
    DOI:  https://doi.org/10.1126/science.abq1053
  14. Biochim Biophys Acta Rev Cancer. 2023 Sep 15. pii: S0304-419X(23)00136-1. [Epub ahead of print] 188987
    The dual role of citrate in cancer.
    Philippe Icard, Luca Simula, Grit Zahn, Marco Alifano, Maria E Mycielska.
      Citrate is a key metabolite of the Krebs cycle that can also be exported in the cytosol, where it performs several functions. In normal cells, citrate sustains protein acetylation, lipid synthesis, gluconeogenesis, insulin secretion, bone tissues formation, spermatozoid mobility, and immune response. Dysregulation of citrate metabolism is implicated in several pathologies, including cancer. Here we discuss how cancer cells use citrate to sustain their proliferation, survival, and metastatic progression. Also, we propose two paradoxically opposite strategies to reduce tumour growth by targeting citrate metabolism in preclinical models. In the first strategy, we propose to administer in the tumor microenvironment a high amount of citrate, which can then act as a glycolysis inhibitor and apoptosis inducer, whereas the other strategy targets citrate transporters to starve cancer cells from citrate. These strategies, effective in several preclinical in vitro and in vivo cancer models, could be exploited in clinics, particularly to increase sensibility to current anti-cancer agents.
    Keywords:  Cancer; Citrate; Drug resistance; Warburg effect; pmCiC
    DOI:  https://doi.org/10.1016/j.bbcan.2023.188987
  15. Endocrinology. 2023 Sep 20. pii: bqad140. [Epub ahead of print]
    Targeting the NAD+ Salvage Pathway: Synergistic Therapeutic Strategy for ER+ Metastatic Breast Cancer.
    Rebecca B Riggins, Suman Ranjit.
      
    Keywords:   ESR1 mutant metastatic breast cancer; fluorescence lifetime imaging microscopy; fulvestrant; metabolic reprogramming; nicotinamide phosphoribosyltransferase
    DOI:  https://doi.org/10.1210/endocr/bqad140
  16. Trends Cell Biol. 2023 Sep 16. pii: S0962-8924(23)00166-6. [Epub ahead of print]
    Spermidine - an old molecule with a new age-defying immune function.
    Kenji Chamoto, Baihao Zhang, Masaki Tajima, Tasuku Honjo, Sidonia Fagarasan.
      Polyamines - putrescine, spermidine, and spermine - are widely distributed aliphatic compounds known to regulate important biological processes in prokaryotic and eukaryotic cells. Therefore, spermidine insufficiency is associated with various physio-pathological processes, such as aging and cancers. Recent advances in immuno-metabolism and immunotherapy shed new light on the role of spermidine in immune cell regulation and anticancer responses. Here, we review novel works demonstrating that spermidine is produced by collective metabolic pathways of gut bacteria, bacteria-host co-metabolism, and by the host cells, including activated immune cells. We highlight the effectiveness of spermidine in enhancing antitumor responses in aged animals otherwise nonresponsive to immune checkpoint therapy and propose that spermidine supplementation could be used to enhance the efficacy of anti-PD-1 treatment.
    Keywords:  antitumor immunity; collective metabolic pathways; fatty acid oxidation; immuno-metabolites; mitochondria; spermidine
    DOI:  https://doi.org/10.1016/j.tcb.2023.08.002
  17. Front Immunol. 2023 ;14 1251643
    Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer.
    Renhong Huang, Han Wang, Jin Hong, Jiayi Wu, Ou Huang, Jianrong He, Weiguo Chen, Yafen Li, Xiaosong Chen, Kunwei Shen, Zheng Wang.
       Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.
    Methods: In this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.
    Results: We found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.
    Conclusions: Hence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC.
    Keywords:  SLC7A5; glutamine metabolism; immunotherapy; synergic effect; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fimmu.2023.1251643
  18. Nat Cancer. 2023 Sep 18.
    PD-1 instructs a tumor-suppressive metabolic program that restricts glycolysis and restrains AP-1 activity in T cell lymphoma.
    Tim Wartewig, Jay Daniels, Miriam Schulz, Erik Hameister, Abhinav Joshi, Joonhee Park, Emma Morrish, Anuroop V Venkatasubramani, Filippo M Cernilogar, Frits H A van Heijster, Christian Hundshammer, Heike Schneider, Filippos Konstantinidis, Judith V Gabler, Christine Klement, Henry Kurniawan, Calvin Law, Yujin Lee, Sara Choi, Joan Guitart, Ignasi Forne, Jérôme Giustinani, Markus Müschen, Salvia Jain, David M Weinstock, Roland Rad, Nicolas Ortonne, Franz Schilling, Gunnar Schotta, Axel Imhof, Dirk Brenner, Jaehyuk Choi, Jürgen Ruland.
      The PDCD1-encoded immune checkpoint receptor PD-1 is a key tumor suppressor in T cells that is recurrently inactivated in T cell non-Hodgkin lymphomas (T-NHLs). The highest frequencies of PDCD1 deletions are detected in advanced disease, predicting inferior prognosis. However, the tumor-suppressive mechanisms of PD-1 signaling remain unknown. Here, using tractable mouse models for T-NHL and primary patient samples, we demonstrate that PD-1 signaling suppresses T cell malignancy by restricting glycolytic energy and acetyl coenzyme A (CoA) production. In addition, PD-1 inactivation enforces ATP citrate lyase (ACLY) activity, which generates extramitochondrial acetyl-CoA for histone acetylation to enable hyperactivity of activating protein 1 (AP-1) transcription factors. Conversely, pharmacological ACLY inhibition impedes aberrant AP-1 signaling in PD-1-deficient T-NHLs and is toxic to these cancers. Our data uncover genotype-specific vulnerabilities in PDCD1-mutated T-NHL and identify PD-1 as regulator of AP-1 activity.
    DOI:  https://doi.org/10.1038/s43018-023-00635-7
  19. Science. 2023 Sep 22. 381(6664): 1287-1288
    Metabolic control of antitumor immunity.
    Andromachi Pouikli, Christian Frezza.
      Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation.
    DOI:  https://doi.org/10.1126/science.adk1785
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