Distinct cytokines regulate gene expression and anti-tumor activity in regenerated CD8+ T cells from induced pluripotent stem cells.

Adoptive T cell therapy can induce tumor regression in cancer patients. Tumor-specific CD8+ T cells regenerated from induced pluripotent stem cells (iPSCs), termed regenerated cytotoxic T lymphocytes (CTLs), are promising resources for adoptive T cell therapy. However, little is known about the cytokines that enhance anti-tumor activity of regenerated CTLs. In this study, we examined effects of exogenous cytokines on regenerated CTLs. We found that IL-15 and IL-21 treatment enhanced the anti-tumor activity of regenerated CTLs, and these cells showed distinct gene expression profiles. IL-15-treated regenerated CTLs exhibited early-effector-like characteristics, whereas IL-21-treated regenerated CTLs exhibited both naive- and effector-like characteristics. Furthermore, we investigated effects of cytokine transduction on regenerated CTLs. IL-2, IL-7, or IL-15 transduction, but not IL-21 transduction, enhanced the survival and cytotoxic activity of regenerated CTLs. Importantly, IL-7 transduction improved the anti-tumor activity of regenerated CTLs in vivo. These findings provide insights for the clinical application of regenerated CTLs.