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ICOS

Inducible T-cell co-stimulator (ICOS), an activating receptor, promotes activation and survival of cytotoxic and memory T cells. Stimulation of ICOS may promote T-cell activation and proliferation.

Expression and normal function

ICOS is an activating receptor from the CD28 superfamily^1-5

ICOS is expressed on activated cytotoxic T cells, regulatory T cells (Tregs),
NK cells, and other types of T cells^1-5
ICOSL (B7RP-1), the ligand for ICOS, is expressed on antigen-presenting cells
(APCs) such as dendritic cells (DCs) and macrophages^1,2,4

While similar in structure to the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor, ICOS has a distinctly opposing function: ICOS/ICOSL signaling leads to the activation, proliferation, and survival of cytotoxic T cells, as well as memory T-cell survival^2,6-9
Following T-cell activation, ICOS upregulation perpetuates T-cell proliferation and function^7,10
ICOS/ICOSL signaling may also enhance activated NK-cell function⁵

Mouse models show that ICOS expression augments the antitumor response of NK cells⁵

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Preclinical evidence

In preclinical studies, ICOS signaling enhanced the activation, proliferation, and function of cytotoxic T cells^11,12
ICOS stimulation in combination with other checkpoint inhibitors was shown to enhance T-cell activity¹¹

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REFERENCES–ICOS

1. Harada H, Salama AD, Sho M, et al. The role of the ICOS-B7h T cell costimulatory pathway in transplantation immunity. J Clin Invest. 2003;112(2):234-243. 2. Zheng J, Chan P-L, Li u Y, et al. ICOS regulates the generation and function of human CD4+ Treg in a CTLA-4 dependent manner. PLoS One. 2013;8(12):e82203. doi:10.1371/journal.pone.0082203. 3. Tu J-F, Ding Y-H, Ying X-H, et al. Regulatory T cells, especially ICOS+ FOXP3+ regulatory T cells, are increased in the hepatocellular carcinoma microenvironment and predict reduced survival. Sci Rep. 2016;6:35056. doi:10.1038/srep35056. 4. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515-548. 5. Ogasawara K, Yoshinaga SK, Lanier LL. Inducible costimulator costimulates cytotoxic activity and IFN-γ production in activated murine NK cells. J Immunol. 2002;169(7):3676-3685. 6. Burmeister Y, Lischke T, Dahler AC, et al. ICOS controls the pool size of effector-memory and regulatory T cells. J Immunol. 2008;180(2):774-782. 7. Hutloff A, Dittrich AM, Beier KC, et al. ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature. 1999;397(6716):263-266. 8. Yoshinaga SK, Whoriskey JS, Khare SD, et al. T-cell co-stimulation through B7RP-1 and ICOS. Nature. 1999;402(6763):827-832. 9. Rudd CE, Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol. 2003;3(7):544-556. 10. Dong C, Juedes AE, Temann U-A, et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature. 2001;409(6816):97-101. 11. Fan X, Quezada SA, Sepulveda MA, Sharma P, Allison JP. Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med. 2014;211(4):715-725. 12. Fu T, He Q, Sharma P. The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti–CTLA-4 therapy. Cancer Res. 2011;71(16):5445-5454.