CD4 T cells require ICOS-mediated PI3K signaling to increase T-Bet expression in the setting of anti-CTLA-4 therapy

Cancer Immunol Res. 2014 Feb;2(2):167-76. doi: 10.1158/2326-6066.CIR-13-0155. Epub 2013 Nov 19.


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-γ. 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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • CD4-Positive T-Lymphocytes / immunology*
  • CTLA-4 Antigen / antagonists & inhibitors
  • CTLA-4 Antigen / immunology
  • Carcinoma, Transitional Cell / drug therapy*
  • Carcinoma, Transitional Cell / immunology
  • Carcinoma, Transitional Cell / pathology
  • Cytokines / biosynthesis
  • Humans
  • Immunotherapy / methods
  • Inducible T-Cell Co-Stimulator Ligand / genetics
  • Inducible T-Cell Co-Stimulator Ligand / immunology*
  • Ipilimumab
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Melanoma / pathology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasm Transplantation
  • Phosphatidylinositol 3-Kinases / immunology*
  • RNA, Small Interfering / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • T-Box Domain Proteins / metabolism
  • Th1 Cells / immunology


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • CTLA-4 Antigen
  • Cytokines
  • ICOSLG protein, human
  • Inducible T-Cell Co-Stimulator Ligand
  • Ipilimumab
  • RNA, Small Interfering
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Phosphatidylinositol 3-Kinases