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

Lu, Yong, Hong, Bangxing, Li, Haiyan, Zheng, Yuhuan, Zhang, Mingjun, Wang, Siqing, Qian, Jianfei, Yi, Qing
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.6 pp. 2265-2270
T-lymphocytes, cytotoxicity, immune response, immunotherapy, interferon-gamma, interleukin-2, interleukin-9, melanoma, models, phenotype
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-1 ˡᵒʷ and IL-7Rα ʰⁱᵍʰ, 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.