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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

Author:
Lu, Yong, Hong, Bangxing, Li, Haiyan, Zheng, Yuhuan, Zhang, Mingjun, Wang, Siqing, Qian, Jianfei, Yi, Qing
Source:
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.6 pp. 2265-2270
ISSN:
0027-8424
Subject:
T-lymphocytes, cytotoxicity, immune response, immunotherapy, interferon-gamma, interleukin-2, interleukin-9, melanoma, models, phenotype
Abstract:
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.
Agid:
2302926