B7-H2/ICOS L and ICOS Promote T Cell Activation
Binding of B7-H2 to ICOS Delivers a T Cell Co-stimulatory Signal
ICOS is another CD28 family receptor that is primarily expressed on activated T cells. It binds to B7-H2/ICOS L expressed on antigen-presenting cells and promotes T cell proliferation and increased cytokine production by Th1 and Th2 cells.1 Conversely, the ICOS/ICOS L pathway has also been shown to enhance the development and activity of regulatory T cells, suggesting that it may have pro-tumor effects as well.2, 3 In a mouse model of melanoma, ICOS or ICOS L knockout mice elicited a reduced response to anti-CTLA-4 therapy, while in other tumor models, ICOS co-stimulation in combination with CTLA-4 blockade was shown to enhance the anti-tumor immune response.4-7 In contrast to these results, ICOS and ICOS L have also both been reported to be expressed on different types of cancer cells and tumor-infiltrating immune cells, and to be associated with tumor progression and poor overall survival.2, 8, 9 Therefore, both agonist and antagonist antibodies targeting the ICOS/ICOSL pathway are still being evaluated for cancer treatment.5
B7-H2 Regulates T Cell Activation by Binding to ICOS
Binding of B7-H2/ICOS L to T cell-expressed ICOS delivers a T cell co-stimulatory signal that enhances Th1 and Th2 cytokine production. Following TCR activation, ICOS is expressed on activated T cells, and is further enhanced upon CD28 co-stimulation. Binding of ICOS to its ligand, B7-H2/ICOS L, which is expressed on antigen-presenting cells (APCs), delivers a co-stimulatory signal that enhances the production of cytokines by Th1 and Th2 cells. Conversely, ICOS L/ICOS signaling may also enhance the development and activity of regulatory T cells in the tumor microenvironment, which may contribute to the suppression of anti-tumor immune responses.
Assessment of the Bioactivity and Purity of R&D Systems B7-H2 and ICOS Proteins
B7-H2/ICOS L Stimulates Anti-CD3-Induced Human T Cell Proliferation. Human T cells were incubated with an immobilized Mouse Anti-Human CD3 epsilon Monoclonal Antibody (R&D Systems, Catalog # MAB100; 20 ng/mL) and the indicated concentrations of Recombinant Human B7-H2/ICOS L Fc Chimera (R&D Systems, Catalog # 165-B7) and cell proliferation was assessed. The ED50 for this effect is typically 0.3-1.2 ug/mL.
Assessment of the Purity of Recombinant Human ICOS by CE-SDS on the MauriceTM System. The purity of Recombinant Human ICOS His tag (R&D Systems, Catalog # 9865-CS) was assessed by capillary electrophoresis (CE)-SDS on the Maurice System under reducing (R) and non-reducing (NR) conditions and visualized in Compass for iCE software. The gel view is shown as an inset with the relative migration time (RMT) on the electropherogram shown on the far right-hand side of the gel.
1. Burugu, S. et al (2017) Emerging targets in cancer immunotherapy. Semin. Cancer Biol. 52 39 PMID: 28987965
2. Martin-Orozco, N. et al (2010) Melanoma cells express ICOS ligand to promote the activation and expansion of T-regulatory cells. Cancer Res. 70 9581 PMID: 21098714
3. Marinelli, O. et al (2018) ICOS-L as a potential therapeutic target for cancer immunotherapy. Curr. Protein Pept. Sci. 19 1107 PMID: 29879883
4. Fu, T. et al (2011) The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res. 71 5445 PMID: 21708958
5. Fan, X. et al (2014) Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J. Exp. Med. 211 715 PMID: 24687957
6. Amatore, F. et al (2018) Inducible co-stimulator (ICOS) as a potential therapeutic target for anti-cancer therapy. Expert. Opin. Ther. Targets 22 343 PMID: 29468927
7. Soldevilla, M.M. et al (2019) ICOS costimulation at the tumor site in combination with CTLA-4 blockade therapy elicits strong tumor immunity. Mol. Ther. 27 1878 PMID: 31405808
8. Faget, J. et al (2012) ICOS-ligand expression on plasmacytoid dendritic cells supports breast cancer progression by promoting the accumulation of immunosuppressive CD4+ T cells. Cancer Res. 72 6130 PMID: 23026134