Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure

Article Article scientifique Article Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure eng 2025-05-20 author Hope Helen Carrasco 0000-0001-5583-4510 Department of Oncology, University of Lausanne, Lausanne, Switzerland. helen.carrascohope@unil.ch.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. helen.carrascohope@unil.ch. author De Sostoa Jana Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland.,Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland. 947937 Département de médecine (DEMED) author Ginefra Pierpaolo 0000-0003-3254-1269 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. author Andreatta Massimo 0000-0002-8036-2647 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland. 435130 Département de pathologie et immunologie (PATIM) author Chiang Yi-Hsuan Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. author Ronet Catherine Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. author Pich-Bavastro Christine 0000-0002-6526-749X Department of Dermatology and Venereology, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland. author Corria Osorio Jesús 0000-0001-6844-6170 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland. author Kuonen François 0000-0001-6137-7483 Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland.,Department of Dermatology and Venereology, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland. author Auwerx Johan Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. author D'Amelio Patrizia Service of Geriatric Medicine and Geriatric Rehabilitation, Department of Internal Medicine, University of Lausanne Hospital Centre (CHUV), Lausanne, Switzerland. author Ho Ping-Chih 0000-0003-3078-3774 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. author Carmona Santiago 0000-0002-2495-0671 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland. 433334 Département de pathologie et immunologie (PATIM) author Coukos George 0000-0001-8813-7367 Department of Oncology, University of Lausanne, Lausanne, Switzerland.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.,Agora Cancer Research Center, Lausanne, Switzerland.,Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland. author Migliorini Denis 0000-0003-0151-3222 Department of Oncology, Geneva University Hospitals (HUG), Geneva, Switzerland. denis.migliorini@unige.ch.,Agora Cancer Research Center, Lausanne, Switzerland. denis.migliorini@unige.ch.,Swiss Cancer Center Léman (SCCL), Lausanne and Geneva, Geneva, Switzerland. denis.migliorini@unige.ch.,Center for Translational Research in Onco-Hematology, University of Geneva, Geneva, Switzerland. denis.migliorini@unige.ch. 838158 Département de médecine (DEMED) author Vannini Nicola 0000-0002-6351-7512 Department of Oncology, University of Lausanne, Lausanne, Switzerland. nicola.vannini@unil.ch.,Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. nicola.vannini@unil.ch. 10.1038/s43018-025-00982-7 40394194 2662-1347 https://www.nature.com/articles/s43018-025-00982-7 Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies. Dewey 616.07 Dewey 616 Swiss Cancer Research Foundation KFS-4993-02-2020-R Leukemia and Lymphoma Society (Leukemia & Lymphoma Society) 6692-25 Swiss National Science Foundation 10.002.388 Swiss Institute for Experimental Cancer Research Foundation Fondation Lionel Perrier Swiss National Science Foundation Genetic control of NAD+ Metabolism 179435 CH Projects Swiss National Science Foundation Targeting cellular senescence in physiological, pathological and iatrogenic conditions 202302 CH Programmes 137 Département de pathologie et immunologie 21F 56 Département de médecine 221 false 1310 Tumeurs cérébrales 1016 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE197268 https://tanlab4generegulation.shinyapps.io/Tcell_Atlas/ Nature cancer f644a178-d344-4a4e-8be9-57d5625043b4 Article (Published version) Public Hope_Nature_Cancer_2025.pdf 11120770 application/pdf CC BY-4.0 f40eaa1fa86b17a355b269e93912232812f7c5f6e2961d71b1eb658e3905b735 8463cf9c-4f47-4b45-8c33-00e16e51f7df Appendix Public 43018_2025_982_MOESM1_ESM.pdf 2813211 application/pdf Reporting summary 8063e6d711538bd02ea7da06cda1d936e73726357cf8e30a08ee7c7b962d6a77 5cd7827e-1f56-4493-879a-0903dc13c5b0 Supplemental data Public 43018_2025_982_MOESM2_ESM.xlsx 39967 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Supplementary Table 1: Metabolomic raw data. Supplementary Table 2: Sequence for CD38 OE vector. ace8e94caafa9c5036242eb04b510631bb8ec2b1cfc42b71da27527b2f42513f bb01ce9e-7bb2-49ee-8422-57f1ab0a183a Supplemental data Public 43018_2025_982_MOESM3_ESM.xlsx 15955 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 1 23f4586fac8c31f31dcfa99dd28362879db2873e0d0431242dc9c9501e14624c 8c61b20a-3c25-4c9f-b892-086de851abec Supplemental data Public 43018_2025_982_MOESM4_ESM.xlsx 14539 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 2 79f023fd56ea313aa866c9dd91a03713e6b0644bb8d985bf720ecfdf1518a237 18df4413-46c9-495c-b3b6-5af403e72043 Supplemental data Public 43018_2025_982_MOESM5_ESM.xlsx 17230 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 3 7d3e3c845b7921ed003099da19efceca63346e92120af57609ab9c6f4b2af1f2 77ffed3a-bd68-4c4a-a4ee-56500e013375 Supplemental data Public 43018_2025_982_MOESM6_ESM.xlsx 27146 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 4 8872ca50aa4c98c303bbeda391666072a1b38ad3eb8ae262e6ef48e6bba2b371 93d82714-06cf-4ae5-8c69-20e4d58d01fe Supplemental data Public 43018_2025_982_MOESM7_ESM.xlsx 46246 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Fig. 5 2844d9d38cf85e927811e9482655fd7c1e5ce083ad8128bc1525731c1238910e 1f22d2ad-f064-45d0-8299-a972e771c871 Supplemental data Public 43018_2025_982_MOESM8_ESM.xlsx 25267 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 1 49a4efc8673808ec4a24623cf18b2e24d46ab3f3bf124a8a8610dbdc3a52a4bc d0a257bb-f68c-4cfb-a060-caac38b3d3c6 Supplemental data Public 43018_2025_982_MOESM9_ESM(2).xlsx 19615 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 3 c8c72bcff57f0d8009274bd321c812862b45607029da4cd62217c3fb969a8ab7 3b31d141-0af7-44c2-9bd6-7f4ae2bc96f1 Supplemental data Public 43018_2025_982_MOESM10_ESM.xlsx 15863 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 4 76479eab33e6ab574bfe7b98f819e5f9c740bf4146e953f16a757f63b74e5eba ccfc681c-f6d9-4e18-a104-3119405120fc Supplemental data Public 43018_2025_982_MOESM11_ESM.xlsx 11355 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 5 8c30a6b75d566027f0559b7f48e85a4dc8147dd4e5ab3d69f5fd96e1b8e74c67 80cc7781-8980-4ecc-a259-78b911b0e453 Supplemental data Public 43018_2025_982_MOESM12_ESM.xlsx 13621 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 6 49ee6cd5360c162a017899f66be62691813fd4f56723eb9cd9f8ebee0610fa5b 4244c114-4bbd-4ac8-bec4-838a70643a6c Supplemental data Public 43018_2025_982_MOESM13_ESM.xlsx 108905 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 7 f37409c71f704fcf36df7640b56062061c727eecda6a32ca8d88d50a1640c491 ff5da903-b8cb-456e-a000-c461577b6e6f Supplemental data Public 43018_2025_982_MOESM14_ESM.xlsx 23644 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet Source Data Extended Data Fig. 8 31d0ab003520b60fd5b7a74bfd1b39cc43b85d1eb39d291556c583b415bcc5f1 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de médecine

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Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure	Nature cancer	2025	76	206
Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors	International Journal of Molecular Sciences	2020	299	501

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