title: ICOS Promotes the Function of CD4+ Effector T Cells during Anti-OX40-Mediated Tumor Rejection.
abstract: ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. Antitumor immunity can be improved by ICOS-targeting therapies, but their mechanism of action remains unclear. Here, we define the role of ICOS signaling in antitumor immunity using a blocking, nondepleting antibody against ICOS ligand (ICOS-L). ICOS signaling provided critical support for the effector function of CD4(+) Foxp3(-) T cells during anti-OX40-driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (Treg), but it was insufficient to substantially inhibit tumor growth. Furthermore, it did not impede antitumor responses mediated by anti-4-1BB-driven CD8(+) T cells. We found that anti-OX40 efficacy, which is based on Treg depletion and to a large degree on CD4(+) effector T cell (Teff) responses, was impaired with ICOS-L blockade. In contrast, the provision of additional ICOS signaling through direct ICOS-L expression by tumor cells enhanced tumor rejection and survival when administered along with anti-OX40 therapy. Taken together, our results showed that ICOS signaling during antitumor responses acts on both Teff and Treg cells, which have opposing roles in promoting immune activation. Thus, effective therapies targeting the ICOS pathway should seek to promote ICOS signaling specifically in effector CD4(+) T cells by combining ICOS agonism and Treg depletion. Cancer Res; 76(13); 3684-9. ©2016 AACR.
authors.affiliation: Rinat Laboratories, Pfizer Inc., South San Francisco, California. Todd.Metzger@pfizer.com Reid.Feldman@pfizer.com.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Metzger
authors.affiliation: Rinat Laboratories, Pfizer Inc., South San Francisco, California.
authors.forename: Hua
authors.initials: H
authors.lastname: Long
authors.affiliation: Rinat Laboratories, Pfizer Inc., South San Francisco, California.
authors.forename: Shobha
authors.initials: S
authors.lastname: Potluri
authors.affiliation: Rinat Laboratories, Pfizer Inc., South San Francisco, California.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pertel
authors.affiliation: Rinat Laboratories, Pfizer Inc., South San Francisco, California.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Bailey-Bucktrout
authors.affiliation: Rinat Laboratories, Pfizer Inc., South San Francisco, California.
authors.forename: John C
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tihui
authors.initials: T
authors.lastname: Fu
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: Rinat Laboratories, Pfizer Inc., South San Francisco, California. Todd.Metzger@pfizer.com Reid.Feldman@pfizer.com.
authors.forename: Reid M R
authors.initials: RM
authors.lastname: Feldman
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40 / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40