Reductive carboxylation epigenetically instructs T cell differentiation

Article Article scientifique Article Reductive carboxylation epigenetically instructs T cell differentiation eng 2023-09-20 2023-09-28 author Jaccard Alison Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland. author Wyss Tania Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Translational Data Science (TDS) Group, AGORA Cancer Research Center, Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. author Maldonado-Perez Noëlia 0000-0001-5975-0488 Department of Genomic Medicine, Pfizer-University of Granada-Junta de Andalucía, Centre for Genomics and Oncological Research (GENYO), Granada, Spain. 412875 Département de médecine (DEMED) author Rath Jan A Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland.,Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,AGORA Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman, Lausanne, Switzerland. author Bevilacqua Alessio 0000-0001-7009-4362 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland. author Peng Jhan-Jie 0000-0001-8923-9234 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland.,Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan. author Lepez Anouk 0000-0002-9612-0706 AGORA Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman, Lausanne, Switzerland.,Brain Tumor and Immune Cell Engineering Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland. 960733 author Von Gunten Christine Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland.,Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,AGORA Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman, Lausanne, Switzerland. author Franco Fabien Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland. author Kao Kung-Chi 0000-0002-5756-6684 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland. author Camviel Nicolas Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland.,Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,AGORA Cancer Research Center, Lausanne, Switzerland. author Martín Francisco 0000-0003-1961-8612 Department of Genomic Medicine, Pfizer-University of Granada-Junta de Andalucía, Centre for Genomics and Oncological Research (GENYO), Granada, Spain. author Ghesquière Bart 0000-0003-1547-1705 Metabolomics Expertise Center, Center for Cancer Biology, VIB, KU Leuven, Leuven, Belgium.,Laboratory of Applied Mass Spectrometry, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. author Migliorini Denis AGORA Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman, Lausanne, Switzerland.,Brain Tumor and Immune Cell Engineering Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland.,Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland. 838158 Département de médecine (DEMED) author Arber Caroline 0000-0001-6440-9970 Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland.,Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.,AGORA Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman, Lausanne, Switzerland. author Romero Pedro 0000-0002-9688-2882 Department of Oncology, University of Lausanne, Lausanne, Switzerland. pedro.romero@unil.ch. author Ho Ping-Chih 0000-0003-3078-3774 Department of Oncology, University of Lausanne, Lausanne, Switzerland. ping-chih.ho@unil.ch.,Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Épalinges, Switzerland. ping-chih.ho@unil.ch. author Wenes Mathias 0000-0001-8478-8592 Department of Oncology, University of Lausanne, Lausanne, Switzerland. mathias.wenes@unige.ch.,AGORA Cancer Research Center, Lausanne, Switzerland. mathias.wenes@unige.ch.,Swiss Cancer Center Léman, Lausanne, Switzerland. mathias.wenes@unige.ch.,Brain Tumor and Immune Cell Engineering Group, Faculty of Medicine, University of Geneva, Geneva, Switzerland. mathias.wenes@unige.ch.,Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland. mathias.wenes@unige.ch. 983986 Département de médecine (DEMED) 849-856 10.1038/s41586-023-06546-y 37730993 0028-0836 https://www.nature.com/articles/s41586-023-06546-y 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. CD8-Positive T-Lymphocytes Cell Differentiation / genetics Citric Acid Cycle Immunologic Memory / genetics Lymphocyte Activation Oxidative Phosphorylation Dewey 616 Swiss National Science Foundation Memory Formation Assessment in Tumor Resident CD8 T Cells (Memory FATE) 182735 CH Projects Oncosuisse KFS-4404-02-2018 European Commission Integration and adaptation of impaired mitochondrial fitness in orchestrating T cell dysfunction in the tumor microenvironment 802773 MitoGuide EU H2020 Swiss National Science Foundation Role of metabolic crosstalk between immune and cancer cells in restricting host anti-tumor immunity and its implications in cancer immunotherapy 182470 CH Projects Swiss Cancer Research KFS-4542-08-2018-R 56 Département de médecine 221 false 1310 Tumeurs cérébrales 1016 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE192395 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE192394 Nature 621 7980 c52b60d9-c890-444d-a8b6-c6fa6f8faa11 Article (Published version) Restricted Jaccard et al. Nature 2023.pdf 12718428 application/pdf fe05a2fd7b2816a39374493a6fb83cc60fd78d5979d95dfcde3cd382a9f3ff8c 6406c1d1-e280-4964-9660-7290ce442cf8 Appendix Restricted 41586_2023_6546_MOESM2_ESM.pdf 117270 application/pdf Reporting summary 6625d4d79d789abf32d771606093a7d84f04a9229741547b89184bd38457fbc2 1b1f26e2-9772-4edd-867a-bb5972206e4a Appendix Restricted 41586_2023_6546_MOESM1_ESM.pdf 1681981 application/pdf Suppl. Figure 1: figures exemplifying the flow cytometry gating strategies for mouse and human cells. 4286d01f1107ba23d3bf12fa176d470871380b00354199e020fc4da8806c357f 15e66541-6ad7-4f8f-bef0-0211ee305441 Appendix Restricted 41586_2023_6546_MOESM3_ESM.pdf 5993379 application/pdf Suppl. Figure 2: Uncropped immunoblot images with size marker indications. b6b058d3f66c01d6effcd7d7455326f007e69cae9d8490fc0ae325d3ac3fb68d ed52d8f5-2367-4336-97bc-db98e11c54f6 Supplemental data Restricted 41586_2023_6546_MOESM4_ESM.xlsx 13008 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 1 89120a1f1c5dfc058ec1bdaa5ecc2157ea9edd1331bdea1f437fc76679f0691a edfebe90-5a18-4e7c-ab3d-e8c9d2384d79 Supplemental data Restricted 41586_2023_6546_MOESM5_ESM.xlsx 22146 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 2 5de60ff66df02a16e19ea76bf0a78babbca07274c80ffd963199cce277b112dd e290c9be-f45b-45c8-99e2-6db24d23c0d5 Supplemental data Restricted 41586_2023_6546_MOESM6_ESM.xlsx 9737 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 3 0e6d5e90e5de38e6fcd761705812506f43896035c9ea6e6b46ee82b82df1b9e8 51b5eae3-8b1e-4481-acdd-2cb0c85518a6 Supplemental data Restricted 41586_2023_6546_MOESM7_ESM.xlsx 15119 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 4 3dd051df000e9dbe42bbef03c7c844f0fa6f4e35e74b3d3f8b657489ce31b2db c185cb85-d477-4825-9776-bd7b58185e8e Supplemental data Restricted 41586_2023_6546_MOESM8_ESM.xlsx 13988 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 1 ff9e4a7b4b136c7e819ca5d743e8fbd7f0ac5a89ed19ce6c96c09522a0bc0dbb 4d694be9-284e-4863-97ad-6bf6cfba9641 Supplemental data Restricted 41586_2023_6546_MOESM9_ESM.xlsx 12418 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 2 b43b9f12b7f5348d9f5d289fe4ee8649226c828350f5ab4b5b8c7f732eb4a342 5633e792-1dba-4526-a578-e439a29b872f Supplemental data Restricted 41586_2023_6546_MOESM10_ESM.xlsx 11367 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 3 fd408d91b77f232f61bb8771fbb732b8ae654919cebbe1b3f7f7b3555b434a51 1620e939-c7d7-4a63-8ffe-1c144cbc7bee Supplemental data Restricted 41586_2023_6546_MOESM11_ESM.xlsx 10844 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 4 cdddf1691f78ed14c32d3051a41371964ecbc058b158b9af454e27257afeb454 070bc63d-6abf-4a94-8c89-198857c621e2 Supplemental data Restricted 41586_2023_6546_MOESM12_ESM.xlsx 18270 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 5 60dd06161c3d5ba4aebd828c9d1c9e54cde749392b06a8bc0374cc51098174b0 2ba215b3-5795-47e4-b6a3-3e986af7c287 Supplemental data Restricted 41586_2023_6546_MOESM13_ESM.xlsx 18371 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 6 b20e4f8f4b08a0122b395098435061c1f2bd28a0618185bc44c7393d14cf64fd 743036b2-6458-4f6d-8ea4-979939564f7b Supplemental data Restricted 41586_2023_6546_MOESM14_ESM.xlsx 11030 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 7 d6fbb80d2c574a418492feff6e34aba2fe2f799c76c027c270cf0234c60b4c49 c7ee78c9-d793-4b1c-b732-cb4348d2fe87 Supplemental data Restricted 41586_2023_6546_MOESM15_ESM.xlsx 17154 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 8 ef0941ab595ebc4c9ac128c5f0b8de1aae071ab65c83d22f37a3f9437e70ed06 201ecced-9640-471e-89d5-cad21a284d6c Supplemental data Restricted 41586_2023_6546_MOESM16_ESM.xlsx 11932 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 9 a1ebf875b49cdc28693e38886105da3da4248931d8dd19b5d548b982d36bb780 35fe8925-3a5e-4bf9-9f74-46828ed12daa Supplemental data Restricted 41586_2023_6546_MOESM17_ESM.xlsx 17279 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 10 e9041aba2f9b4854807cbfddfb7a52b39579cbaf81a994db037cc515fd013139 restrictedAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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