IL-15 enhances the antitumor effect of human antigen-specific CD8+ T cells by cellular senescence delay

Jinsheng Weng, Kelsey E Moriarty, Flavio Egidio Baio, Fuliang Chu, Sung-Doo Kim, Jin He, Zuliang Jie, Xiaoping Xie, Wencai Ma, Jianfei Qian, Liang Zhang, Jing Yang, Qing Yi, Sattva S Neelapu, Larry W Kwak

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Optimal expansion protocols for adoptive human T-cell therapy often include interleukin (IL)-15; however, the mechanism by which IL-15 improves the in vivo antitumor effect of T cells remains to be elucidated. Using human T cells generated from HLA-A2+ donors against novel T-cell epitopes derived from the human U266 myeloma cell line Ig light chain V-region (idiotype) as a model, we found that T cells cultured with IL-15 provided superior resistance to tumor growth in vivo, compared with IL-2, after adoptive transfer into immunodeficient hosts. This effect of IL-15 was associated with delayed/reversed senescence in tumor antigen-specific memory CD8+ T cells mediated through downregulation of P21WAF1, P16INK4a, and P53 expression. Compared to IL-2, IL-15 stimulation dramatically activated JAK3-STAT5 signaling and inhibited the expression of DNA damage genes. Thus, our study elucidates a new mechanism for IL-15 in the regulation of STAT signaling pathways and CD8+ T-cell senescence.

Original languageEnglish (US)
Pages (from-to)e1237327
JournalOncoImmunology
Volume5
Issue number12
DOIs
StatePublished - 2016

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