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Continuous antigen exposure drives CAR T cell exhaustion and promotes CD8+ T-to-NK-like
T cell transition. Transcription factors ID3 and SOX4 are upregulated during CAR dysfunction
and regulate genes associated with exhaustion, including NK receptors. Knocking out
ID3 and SOX4 in CAR T cells slows dysfunction and improves anti-tumor immunity.
CAR T cells have proven to be a powerful weapon against blood cancers, but against solid tumors they are much less effective, in part because of a process called T cell exhaustion. However, Penn Medicine researchers have uncovered key molecular details of this exhaustion process that point to a specific strategy to overcome it. In this study, the scientists developed a labmodel  allowing them to thoroughly study the exhaustion process of CAR T cells designed to attack pancreatic tumors. They observed that the process of T cell exhaustion in the model closely resembled that observed in patient T cells. The model also revealed new facets of the exhaustion process, including the role of 2 genetic regulators of exhaustion, ID3 and SOX4, whose silencing allowed CAR T cells to retain much of their effectiveness against tumor cells. The scientists observed that CAR T cell exhaustion was accompanied by increases in the levels of two proteins, ID3 and SOX4, which function as master switches for large sets of genes in immune cells. Silencing these apparent T-cell exhaustion switches allowed the depleted CAR T cells to retain much of their antitumor efficacy even after prolonged exposure to tumor cells.
The study thus points to a specific strategy - inhibition of ID3 and/or SOX4 - that could help CAR T cells function better against solid tumors.