Abstract
The generation of anti-tumor T-cell responses requires at least two distinct signals consisting of T-cell receptor signaling and CD28-costimulation to mediate PI3-kinase signaling. In previous studies, we reported that cancer patients treated with anti-CTLA-4 had a significant increase in T-cells expressing inducible costimulator (ICOS). Here, we observed that PI3-kinase signaling was significantly increased in ICOShi as compared to ICOSlow CD28+ T-cells from anti-CTLA-4 treated patients. Our data also indicate that after T-cell activation, ICOS-mediated PI3-kinase signaling plays an important role in downstream T-cell responses such as expression of the T-bet transcription factor and anti-tumor Th1 cytokine production. An ICOS-specific siRNA transfected into activated human T-cells leads to diminished PI3K-signaling and T-bet expression, which controls production of anti-tumor Th1 cytokines. Furthermore, T-cells from ICOS-deficient mice have impaired PI3-kinase signaling after in vitro activation. Our data also demonstrate that T-cells from ICOS-deficient mice have impaired PI3-kinase signaling in vivo, which correlates with impaired tumor rejection after treatment with anti-CTLA-4. These data offer strong evidence to support that CD28-mediated PI3-kinase signaling is limited and ICOS provides a critical third signal to enable sustained PI3-kinase signaling for optimal anti-tumor T-cell responses in the setting of anti-CTLA-4 therapy.
Citation Format: Hong Chen, Tihui Fu, Dimitra Tsavachidou, Sijin Wen, Derek Ng Tang, Qiuming He, Jing Jing Sun, Padmanee Sharma. Sustained PI3-kinase signaling is mediated by ICOS, not CD28, for anti-tumor T-cell responses elicited by anti-CTLA-4. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1265. doi:10.1158/1538-7445.AM2013-1265