CD4 T Cells Require ICOS-Mediated PI3K Signaling to Increase T-Bet Expression in the Setting of Anti-CTLA-4 Therapy

被引:48
作者
Chen, Hong [1 ]
Fu, Tihui [1 ]
Suh, Woong-Kyung [5 ]
Tsavachidou, Dimitra [2 ]
Wen, Sijin [4 ]
Gao, Jianjun [1 ]
Tang, Derek Ng [1 ]
He, Qiuming [1 ]
Sun, Jingjing [1 ]
Sharma, Padmanee [1 ,3 ]
机构
[1] Univ Texas Houston, MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX 77030 USA
[2] Univ Texas Houston, MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA
[3] Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA
[4] Univ Virginia, Hlth Sci Ctr, Dept Biostat, Morgantown, WV USA
[5] Univ Montreal, IRCM, Dept Med, Montreal, PQ, Canada
关键词
TRANSCRIPTION FACTOR; DIFFERENTIATION; CANCER; EFFECTOR; IMMUNITY;
D O I
10.1158/2326-6066.CIR-13-0155
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The transcription factor T-bet controls the Th1 genetic program in T cells for effective antitumor responses. Anti-CTLA-4 immunotherapy elicits dramatic antitumor responses in mice and in human patients; however, factors that regulate T-bet expression during an antitumor response mediated by anti-CTLA-4 remain to be elucidated. We were the first to report that treatment with anti-CTLA-4 led to an increase in the frequency of T cells expressing inducible costimulator (ICOS). In both treated patients and mice, our data revealed that CD4(+)ICOS(hi) T cells can act as effector T cells, which produce the Th1 cytokine IFN-gamma. We also showed in a small retrospective analysis that an increased frequency of CD4(+)ICOS(hi) T cells correlated with better clinical outcome and the absence of ICOS or its ligand (ICOSL) in mouse models led to impaired tumor rejection. Here, we show that CD4(+)ICOS(hi) T cells from anti-CTLA-4-treated patients had an increase in signaling via the phospoinositide-3-kinase (PI3K) pathway and an increase in expression of T-bet. An ICOS-specific siRNA transfected into human T cells led to diminished PI3K signaling and T-bet expression. Therefore, we hypothesized that ICOS, and specifically ICOS-mediated PI3K signaling, was required for T-bet expression. We conducted studies in ICOS-deficient and ICOS-YF mice, which have a single amino acid change that abrogates PI3K signaling by ICOS. We found that ICOS-mediated PI3K signaling is required for T-bet expression during an antitumor response elicited by anti-CTLA-4 therapy. Our data provide new insight into the regulation of T-bet expression and suggest that ICOS can be targeted to improve Th1 antitumor responses. (C) 2013 AACR.
引用
收藏
页码:167 / 176
页数:10
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