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Dynamic chromatin regulatory landscape of human CAR T cell exhaustion [Immunology and Inflammation]
Proceedings of the National Academy of Sciences of the United States of America  (IF11.205),  Pub Date : 2021-07-27, DOI: 10.1073/pnas.2104758118
David G. Gennert, Rachel C. Lynn, Jeff M. Granja, Evan W. Weber, Maxwell R. Mumbach, Yang Zhao, Zhana Duren, Elena Sotillo, William J. Greenleaf, Wing H. Wong, Ansuman T. Satpathy, Crystal L. Mackall, Howard Y. Chang

Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and three-dimensional (3D) chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mice, we find that the regulatory networks of T cell exhaustion differ between species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.