Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling

• Published in: Science (American Association for the Advancement of Science) 2021-04, Vol.372 (6537)
• Main Authors: Weber, Evan W, Parker, Kevin R, Sotillo, Elena, Lynn, Rachel C, Anbunathan, Hima, Lattin, John, Good, Zinaida, Belk, Julia A, Daniel, Bence, Klysz, Dorota, Malipatlolla, Meena, Xu, Peng, Bashti, Malek, Heitzeneder, Sabine, Labanieh, Louai, Vandris, Panayiotis, Majzner, Robbie G, Qi, Yanyan, Sandor, Katalin, Chen, Ling-Chun, Prabhu, Snehit, Gentles, Andrew J, Wandless, Thomas J, Satpathy, Ansuman T, Chang, Howard Y, Mackall, Crystal L
• Format: Article
• Language: English
• Subjects: Adoptive transfer; Animal models; Animals; Anticancer properties; Antigen (tumor-associated); Antigens; Antitumor activity; Apoptosis; CAR protein; Cell culture; Cell fate; Cell Line, Tumor; Cell proliferation; Cytotoxicity, Immunologic; Dasatinib - pharmacology; Down-Regulation; Enhancer of Zeste Homolog 2 Protein - metabolism; Enzyme inhibitors; Epigenesis, Genetic; Epigenetics; Epigenome; Female; Genotype & phenotype; Hepatocyte nuclear factor 1; Hepatocyte Nuclear Factor 1-alpha - metabolism; High Mobility Group Proteins - metabolism; Histone methyltransferase; Humans; Immune checkpoint; Immunologic Memory; Immunotherapy; Immunotherapy, Adoptive; Inhibition; Kinases; Logical Thinking; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Lymphoid Enhancer-Binding Factor 1 - metabolism; Male; Memory; Memory cells; Mice; Motor Vehicles; Neoplasms, Experimental - therapy; Patients; Phenotypes; Protein Domains; Protein Stability; Protein-tyrosine kinase; Proteins; Receptors; Receptors, Chimeric Antigen - chemistry; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Signal Transduction; Signaling; Solid tumors; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcription factors; Transcription, Genetic; Tumors; Tyrosine; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aba1786

T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state.