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

Science. 2021 Apr 2;372(6537):eaba1786. doi: 10.1126/science.aba1786.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Dasatinib / pharmacology*
  • Down-Regulation
  • Enhancer of Zeste Homolog 2 Protein / metabolism
  • Epigenesis, Genetic*
  • Epigenome
  • Female
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • High Mobility Group Proteins / metabolism
  • Humans
  • Immunologic Memory
  • Immunotherapy, Adoptive*
  • 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
  • Receptors, Chimeric Antigen / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • Transcription, Genetic
  • Xenograft Model Antitumor Assays

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • High Mobility Group Proteins
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Receptors, Chimeric Antigen
  • TOX protein, human
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Dasatinib