ICOS promotes the function of CD4+ effector T cells during anti-OX40 mediated tumor rejection

ICOS is a T cell co-regulatory 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, non-depleting 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. Further, it did not impede antitumor responses mediated by anti-4-1BB-driven CD8+ T cells. We found that anti-OX40 efficacy, which is based in Treg depltion and to a large degree on CD4+ effector T cells (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.