Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling.
Science (New York, N.Y.)
2021; 372 (6537)
Charting a shared epigenetic pathway to CD8+ T cell dysfunction in infection and cancer.
2021; 81 (11): 2272-2274
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.
View details for DOI 10.1126/science.aba1786
View details for PubMedID 33795428
Pritykin et al. (2021) establish a comprehensive chromatin atlas of CD8+ T cell dysfunction in chronic viral infection and cancer via analysis of bulk and single-cell ATAC-seq datasets across immune challenges. These results unify the classification scheme and molecular programs driving CD8+ T cell dysfunction across disease settings and will facilitate basic discovery and translational efforts in T cell immunity.
View details for DOI 10.1016/j.molcel.2021.05.020
View details for PubMedID 34087178