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.
Author Info: (1) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Ins
Author Info: (1) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: gurusamyd@mail.nih.gov. (2) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (3) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA. (4) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (5) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (6) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (7) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (8) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (9) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (10) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (11) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (12) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (13) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (14) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (15) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (16) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. (17) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: shashank.oxin@gmail.com. (18) Surgery Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Center for Cell-based Therapy, Center for Cancer Research, National Institutes of Health (NIH), Bethesda, MD 20892, USA; Immunology Graduate Group, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: restifon@mail.nih.gov.
