Cytokine gene combination on iPS cell-derived T cells synergistically improves migration, proliferation, and memory formation in solid tumors

T cells show anti-tumor efficacy against solid tumor by infiltration, proliferation, and antigen-specific cytotoxicity. In this study, we investigated various combinations of cytokine gene modifications in chimeric antigen receptor-transfected induced pluripotent stem cell-derived T cells (iCAR-T cells). We found that the combination of interleukin 15 (IL-15) and IL-21 gene modification maintained the infiltration and persistence of iCAR-T cells in tumors and significantly prolonged the survival of a subcutaneous tumor-bearing mouse model. As a novel finding, this combination promoted phosphorylation of STAT1 and enhanced the binding of CXCR3 to its promoter region. Furthermore, iCAR-T cells expressing IL-15 and IL-21 were found to have a gene expression profile similar to primary CD8 CAR-T cells in tumors and to have a memory T-cell-like phenotype. Thus, the IL-15 and IL-21 combination may accelerate the therapeutic efficacy of iCAR-T cells for solid tumor immunotherapies as a substitute of peripheral blood CD8 T cells.