The transcription factor T-bet controls the Th1 genetic program in T cells for effective anti-tumor responses. Anti-CTLA-4 immunotherapy elicits dramatic anti-tumor responses in mice and patients; however, factors that regulate T-bet expression during an anti-tumor 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 the frequency of T cells expressing inducible costimulator (ICOS). In both treated patients and mice our data revealed that CD4+ICOShi T cells can act as effector T cells, which produce the Th1 cytokine interferon gamma (IFNgamma). We also showed in a small restrospective analysis that an increased frequency of CD4+ICOShi 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+ICOShi 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 to abrogate PI3K-signaling by ICOS. We found that ICOS-mediated PI3K-signaling is required for T-bet expression during an anti-tumor 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 anti-tumor responses.
- Received September 17, 2013.
- Revision received October 22, 2013.
- Accepted October 28, 2013.
- Copyright © 2013, American Association for Cancer Research.