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

• Published in: Oncoimmunology 2016-12, Vol.5 (12), p.e1237327-e1237327
• Main Authors: Weng, Jinsheng, Moriarty, Kelsey E., Baio, Flavio Egidio, Chu, Fuliang, Kim, Sung-Doo, He, Jin, Jie, Zuliang, Xie, Xiaoping, Ma, Wencai, Qian, Jianfei, Zhang, Liang, Yang, Jing, Yi, Qing, Neelapu, Sattva S., Kwak, Larry W.
• Format: Article
• Language: English
• Subjects: Idiotype; IL-15; immunotherapy; myeloma; Original Research; senescence; T cells
• ISSN: 2162-4011; 2162-402X; 2162-402X
• DOI: 10.1080/2162402X.2016.1237327

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 P21 WAF1 , P16 INK4a , 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.