CD4 T cells require ICOS-mediated PI3K signaling to increase T-Bet expression in the setting of anti-CTLA-4 therapy.
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.
Authors' Affiliations: IRCM (Institut de recherches cliniques de Montreal) and Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
Hong
H
Chen
Tihui
T
Fu
Woong-Kyung
WK
Suh
Dimitra
D
Tsavachidou
Sijin
S
Wen
Jianjun
J
Gao
Derek
D
Ng Tang
Qiuming
Q
He
Jingjing
J
Sun
Padmanee
P
Sharma
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000276:immunology*; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020825:T-Box Domain Proteins / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D000098815:T-bet Transcription Factor
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D016207:Cytokines; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D000074324:Ipilimumab; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D019869:Phosphatidylinositol 3-Kinases