Using a CRISPR-Cas9-based genetic screen to evaluate targetable kinases in T cells, Gurusamy et al. identified p38 as a key regulator of desirable T cell phenotypes. Knockout of p38 or small molecule inhibition (p38i) increased T cell expansion and differentiation towards memory phenotypes while reducing oxidative stress and DNA damage. T cells cultured with p38i showed increased production of IFNγ and IL-2 in vitro, and superior expansion, persistence, and antitumor efficacy following adoptive transfer into mice. The use of p38i had similar effects in cultures of human T cells, including TCR- and CAR-engineered cells.
Contributed by Lauren Hitchings
ABSTRACT: T cells are central to all currently effective cancer immunotherapies, but the characteristics defining therapeutically effective anti-tumor T cells have not been comprehensively elucidated. Here, we delineate four phenotypic qualities of effective anti-tumor T cells: cell expansion, differentiation, oxidative stress, and genomic stress. Using a CRISPR-Cas9-based genetic screen of primary T cells we measured the multi-phenotypic impact of disrupting 25 T cell receptor-driven kinases. We identified p38 kinase as a central regulator of all four phenotypes and uncovered transcriptional and antioxidant pathways regulated by p38 in T cells. Pharmacological inhibition of p38 improved the efficacy of mouse anti-tumor T cells and enhanced the functionalities of human tumor-reactive and gene-engineered T cells, paving the way for clinically relevant interventions.