1. Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling.
- Author
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Weber EW, Parker KR, Sotillo E, Lynn RC, Anbunathan H, Lattin J, Good Z, Belk JA, Daniel B, Klysz D, Malipatlolla M, Xu P, Bashti M, Heitzeneder S, Labanieh L, Vandris P, Majzner RG, Qi Y, Sandor K, Chen LC, Prabhu S, Gentles AJ, Wandless TJ, Satpathy AT, Chang HY, and Mackall CL
- Subjects
- Animals, Cell Line, Tumor, Cytotoxicity, Immunologic, Down-Regulation, Enhancer of Zeste Homolog 2 Protein metabolism, Epigenome, Female, Hepatocyte Nuclear Factor 1-alpha metabolism, High Mobility Group Proteins metabolism, Humans, Immunologic Memory, Lymphocyte Activation, Lymphoid Enhancer-Binding Factor 1 metabolism, Male, Mice, Neoplasms, Experimental therapy, Protein Domains, Protein Stability, Receptors, Chimeric Antigen chemistry, Receptors, Chimeric Antigen immunology, Signal Transduction, T-Lymphocytes metabolism, Transcription, Genetic, Xenograft Model Antitumor Assays, Dasatinib pharmacology, Epigenesis, Genetic, Immunotherapy, Adoptive, Receptors, Chimeric Antigen metabolism, T-Lymphocytes immunology
- Abstract
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., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2021
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