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IL12 integrated into the CAR exodomain converts CD8+ T cells to poly-functional NK-like cells with superior killing of antigen-loss tumors

ABSTRACT: Chimeric antigen receptor (CAR)-redirected T cell therapy often fails to control tumors in the long-term due to selecting cancer cells that down-regulated or lost CAR targeted antigen. To reprogram the functional capacities of CAR T cells, we inserted IL12 into the extracellular moiety of a CD28- CAR; both the CAR and IL12 were functional indicated by antigen-redirected activation and STAT4 phosphorylation, respectively. CD8+ T cells engineered with a IL12-CAR gained a so far not recognized NK cell-like RNA expression signature and a CD94+CD56+CD62Lhigh phenotype closely similar, but not identical, to NK and cytokine activated killer (CIK) cells. IL12-CAR T cells with specificity for CEA additionally acquired antigen-independent, HLA-E restricted cytotoxicity eliminating both CEA-negative and CEA-positive cancer cells in an antigen-dependent and independent fashion that was in contrast to conventional CEA CAR T cells. Simultaneous signaling through CD3 of the CAR and through IL12 were required and sufficient for inducing NK-like cytotoxicity. Overall, we present a prototype of a new family of CARs that harbor a cytokine integrated into the extracellular module in order to reprogram the functional capacities of CAR T cells towards augmented tumor recognition and elimination.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182623 | GEO | 2021/08/24

REPOSITORIES: GEO

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