[en] T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8+ tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10-Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8+ tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10-Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy.
Disciplines :
Immunology & infectious disease
Author, co-author :
Guo, Yugang ; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Institute of Materials Science & Engineering, EPFL, Lausanne, Switzerland
Xie, Yu-Qing ; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Gao, Min ; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Zhao, Yang; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
Franco, Fabien; Department of Oncology, University of Lausanne, Epalinges, Switzerland ; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
Wenes, Mathias; Department of Oncology, University of Lausanne, Epalinges, Switzerland
Siddiqui, Imran; Department of Oncology, University of Lausanne, Epalinges, Switzerland
Bevilacqua, Alessio ; Department of Oncology, University of Lausanne, Epalinges, Switzerland ; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
Wang, Haiping; Department of Oncology, University of Lausanne, Epalinges, Switzerland ; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
Yang, Hanshuo; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, China
Feng, Bing; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Institute of Materials Science & Engineering, EPFL, Lausanne, Switzerland
Xie, Xin ; Center for Genomics and Systems Biology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
Sabatel, Catherine ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Biochimie et biologie moléculaire ; Department of Oncology, University of Lausanne, Epalinges, Switzerland
Tschumi, Benjamin; Department of Oncology, University of Lausanne, Epalinges, Switzerland
Chaiboonchoe, Amphun ; Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
Wang, Yuxi; Department of Respiratory and Critical Care Medicine, West China Medical School/West China Hospital, Sichuan University, Chengdu, China
Li, Weimin; Department of Respiratory and Critical Care Medicine, West China Medical School/West China Hospital, Sichuan University, Chengdu, China
Xiao, Weihua; Department of Oncology of the First Affiliated Hospital, Division of Life Sciences and Medicine, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
Held, Werner ; Department of Oncology, University of Lausanne, Epalinges, Switzerland
Romero, Pedro ; Department of Oncology, University of Lausanne, Epalinges, Switzerland
Ho, Ping-Chih ; Department of Oncology, University of Lausanne, Epalinges, Switzerland. ping-chih.ho@unil.ch ; Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland. ping-chih.ho@unil.ch
Tang, Li ; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. li.tang@epfl.ch ; Institute of Materials Science & Engineering, EPFL, Lausanne, Switzerland. li.tang@epfl.ch
We thank D. Trono and B.E. Correia for providing plasmids of Delta 8.9 and pVSV-G; J.-C. Martinou (University of Geneva) for providing Mpc1fl/fl mice; and A. Donda (University of Lausanne) for the technical support on human CAR T cells. We acknowledge the EPFL Center of PhenoGenomics, Flow Cytometry Core Facility and Protein Expression Core Facility for technical assistance. This work was supported in part by the Swiss National Science Foundation (SNSF project grant no. 315230_173243), the ISREC Foundation with a donation from the Biltema Foundation, the Swiss Cancer League (grant no. KFS-4600-08-2018), the European Research Council under the ERC grant agreement MechanoIMM (grant no. 805337), the Kristian Gerhard Jebsen Foundation, Fondation Pierre Mercier pour la science, an Anna Fuller Fund grant and the EPFL (L.T.). P.-C.H. was supported in part by the Swiss Institute for Experimental Cancer Research (ISREC grant no. 26075483), SNSF project grants (grant nos. 31003A_163204 and 31003A_182470), the Cancer Research Institute Lloyd J. Old STAR award and the European Research Council Starting Grant (grant no. 802773-MitoGuide). P.R. was supported in part by grants from the SNSF (grant nos. 310030_182735 and 310030E-164187). W.H. was supported in part by the Swiss Cancer League (grant no. KFS-4407-02-2018) and the SNSF (grant no. 310030B_179570). W.X. was supported in part by the Strategic Priority Research Program of the Chinese Academy of Sciences (grant no. XDB29030000) and the Ministry of Science and Technology of China (grant no. 2016YFC1303503). M.G. was supported by the Chinese Scholarship Council (grant no. 201808320453).
