@article{ae1fab29259748c09efd8bd1e4486456,
title = "CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours",
abstract = "Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells1. By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis1. Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8+ T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (Treg) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of Treg cells is dependent on Treg cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with Treg cell function in the presence of glucose.",
author = "Roberta Zappasodi and Inna Serganova and Cohen, {Ivan J.} and Masatomo Maeda and Masahiro Shindo and Yasin Senbabaoglu and Watson, {McLane L.J.} and Avigdor Leftin and Rachana Maniyar and Svena Verma and Matthew Lubin and Myat Ko and Mane, {Mayuresh M.} and Hong Zhong and Cailian Liu and Arnab Ghosh and Mohsen Abu-Akeel and Ellen Ackerstaff and Koutcher, {Jason A.} and Ho, {Ping Chih} and Delgoffe, {Greg M.} and Ronald Blasberg and Wolchok, {Jedd D.} and Taha Merghoub",
note = "Funding Information: Acknowledgements We thank the Flow Cytometry and Integrated Genomics Operation Cores at MSK for technical assistance. We thank A. Rudensky for the constructive discussions for the revisions of this manuscript. This research was funded in part through the NIH/NCI R01 CA215136-01A1 and Cancer Center Support Grant P30 CA008748, the Swim Across America, Ludwig Institute for Cancer Research, Parker Institute for Cancer Immunotherapy and Breast Cancer Research Foundation. R.Z. was supported by the Parker Institute for Cancer Immunotherapy scholar and bridge scholar awards. I.S. was supported by R50 CA221810 (NIH/ NCI) grant. M.J.W. was supported by T32CA082084 and F31AI149971. P.-C.H. was supported by the SNSF project grants (31003A_182470) and European Research Council Staring Grant (802773-MitoGuide). G.M.D. was supported by DP2AI136598 and R21AI135367. Funding Information: Competing interests R.Z. is inventor on patent applications related to work on GITR, PD-1 and CTLA-4. R.Z. is consultant for Leap Therapeutics and iTEOS Belgium SA. Y.S. is currently employed by Genentech and holds equity in Roche. P.-C.H. received research support from Roche-pRED and honorarium from Chungai and Pfizer. P.-C.H. is also a scientific advisory board member of Elixiron Immunotherapeutics and Acepodia. G.M.D. consults for and/or is on the scientific advisory board of BlueSphere Bio, Century Therapeutics, Novasenta, Pieris Pharmaceuticals, and Western Oncolytics/Kalivir; has grants from bluebird bio, Novasenta, Pfizer, Pieris Pharmaceuticals, TCR2, and Kalivir; G.M.D. owns equity in BlueSphere Bio and Novasenta. T.M. is a cofounder and holds an equity in IMVAQ Therapeutics. T.M. is a consultant of Immunos Therapeutics, Pfizer and Immunogenesis. T.M. has research support from Bristol-Myers Squibb; Surface Oncology; Kyn Therapeutics; Infinity Pharmaceuticals, Inc.; Peregrine Pharmaceuticals, Inc.; Adaptive Biotechnologies; Leap Therapeutics, Inc.; and Aprea. T.M. has patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccines, neo-antigen modelling, CD40, GITR, OX40, PD-1 and CTLA-4. J.D.W. is consultant for Adaptive Biotech; Amgen; Apricity; Ascentage Pharma; Astellas; AstraZeneca; Bayer; Beigene; Boehringer Ingelheim; Bristol Myers Squibb; Celgene; Chugai; Eli Lilly; Elucida; F Star; Georgiamune; Imvaq; Kyowa Hakko Kirin; Linneaus; Merck; Neon Therapeutics; Polynoma; Psioxus; Recepta; Takara Bio; Trieza; Truvax; Sellas; Serametrix; Surface Oncology; Syndax; Syntalogic, Werewolf Therapeutics. J.D.W. reports grants from Bristol Myers Squibb and Sephora. J.D.W. has equity in Tizona Pharmaceuticals; Adaptive Biotechnologies; Imvaq; Beigene; Linneaus; Apricity; Arsenal IO; Georgiamune. J.D.W. is inventor on patent applications related to work on DNA vaccines in companion animals with cancer, assays for suppressive myeloid cells in blood, oncolytic viral therapy, alphavirus-based vaccines, neo-antigen modelling, CD40, GITR, OX40, PD-1 and CTLA-4. The other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2021",
month = mar,
day = "25",
doi = "10.1038/s41586-021-03326-4",
language = "English (US)",
volume = "591",
pages = "652--658",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7851",
}