Dynamic chromatin regulatory landscape of human CAR T cell exhaustion

Area of Science:

• Immunology
• Genomics
• Cancer Research

Background:

• T cell dysfunction limits cancer immunotherapy effectiveness.
• Chimeric antigen receptor (CAR) T cells are a promising cancer treatment.
• Understanding T cell exhaustion is crucial for enhancing CAR T cell therapy.

Purpose of the Study:

• To investigate the epigenetic and transcriptomic changes associated with T cell exhaustion in human CAR T cells.
• To compare T cell exhaustion regulatory networks between human and mouse models.
• To identify potential targets for improving CAR T cell function.

Main Methods:

• Profiling of epigenome, transcriptome, and enhancer connectome of HA-28z CAR T cells and control CAR T cells during ex vivo expansion.
• Analysis of chromatin accessibility and 3D chromosome conformation.
• Identification of transcription factor binding motifs and candidate exhaustion-specific enhancers.

Main Results:

• Widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceded gene expression changes.
• Exhaustion-associated genes like PDCD1, CTLA4, and HAVCR2 showed altered chromatin accessibility.
• Human T cell exhaustion involves distinct regulatory networks and gene loci compared to mice.
• Deletion of PDCD1 enhancers suppressed PD-1 expression in a T cell dysfunction model.

Conclusions:

• Epigenetic modifications play a critical role in T cell exhaustion during CAR T cell therapy.
• Human and mouse T cell exhaustion pathways differ, necessitating human-specific research.
• Enhancer editing presents a potential strategy to overcome T cell exhaustion and enhance immunotherapy efficacy.