DeGolier et al. demonstrated that CD8+ T cell antigen experience before CAR transduction promoted effector functions at the expense of proliferative capacity. Memory-derived CAR T cells (CAR8MD) exhibited superior clearance of CD19lo leukemia, but displayed reduced proliferative capacity and susceptibility to exhaustion, in contrast to naive-derived CAR T cells (CAR8ND), which showed enhanced expansion and resistance to exhaustion. Multi-omics profiling revealed that RUNX2 overexpression enhanced the effector function of CAR8ND cells, prevented exhaustion, maintained self-renewal, and improved the function of human and murine CAR T cells.
Contributed by Shishir Pant
ABSTRACT: Although chimeric antigen receptor (CAR) T cells are effective against B-lineage malignancies, post-CAR relapse is common, and efficacy in other tumors is limited. These challenges may be addressed through rational manipulations to control CAR T cell function. Here we examine the impact of cognate T cell antigen experience on subsequent CD8(+) CAR T cell activity. Prior antigen encounter resulted in superior effector function against leukemia expressing low target antigen density at the expense of reduced proliferative capacity and susceptibility to dysfunction at limiting CAR doses. Distinctive temporal transcriptomic and epigenetic profiles in naive-derived and memory-derived CAR T cells identified RUNX family transcription factors as potential targets to augment the function of naive-derived CD8(+) CAR T cells. RUNX2 overexpression enhanced antitumor efficacy of mouse CAR T cells, dependent on prior cell state, and heightened human CAR T cell functions. Our data demonstrate that prior antigen experience of CAR T cells determines functional attributes and amenability to transcription factor-mediated functional enhancement.
Author Info: (1) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO,
Author Info: (1) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (2) Biostatistics and Bioinformatics Shared Resource, University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (3) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (4) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (5) Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA. (6) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. (7) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA. (8) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. Department of Immunology and Genomic Medicine, National Jewish Health, Denver, CO, USA. (9) Department of Immunology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. terry.fry@cuanschutz.edu. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. terry.fry@cuanschutz.edu. Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA. terry.fry@cuanschutz.edu.
