Tumor-specific IL-9-producing CD8⁺ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers

Because cytokine-priming signals direct CD8⁺ T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8⁺ T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8⁺ cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/ B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-γ- and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1low and IL-7Rαhigh, suggesting that they acquired a signature of younger phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8⁺ T-cell-based adoptive immunotherapy of cancers.