Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 30, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2104758118
Keywords
cancer immunotherapy; epigenomics; enhancer editing
Categories
Funding
- Parker Institute for Cancer Immunotherapy
- NIH [RM1-HG007735, R35-CA209919, K08CA230188]
- Cellular and Molecular Immunobiology Training Grant (NIH National Institute of Allergy and Infectious Diseases) [5 T32 AI07290]
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This study identified the limitations of cancer immunotherapy due to T cell dysfunction, and highlighted the potential of enhancer editing as a pathway to improve treatment efficacy, by analyzing epigenomic and transcriptomic changes in different CAR T cells during their expansion process.
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 CART 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 CART 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.
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