Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling
Evan W. Weber, Kevin R. Parker, Elena Sotillo, Rachel C. Lynn, Hima Anbunathan, John Lattin, Zinaida Good, Julia A. Belk, Bence Dániel, Dorota D. Klysz, Meena Malipatlolla, Peng Xu, Malek Bashti, Sabine Heitzeneder, Louai Labanieh, Panayiotis Vandris, Robbie G. Majzner, Yanyan Qi, Katalin Sándor, Ling‐Chun Chen, Snehit Prabhu, Andrew J. Gentles, Thomas J. Wandless, Ansuman T. Satpathy, Howard Y. Chang, Crystal L. Mackall
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.