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 þ Foxp3À T cells during anti-OX40-driven tumor immune responses. By itself, ICOS-L blockade reduced accumulation of intratumoral T regulatory cells (T reg ), but it was insufficient to substantially inhibit tumor growth. Furthermore, it did not impede antitumor responses mediated by anti-4-1BB-driven CD8 þ T cells.We found that anti-OX40 efficacy, which is based on T reg depletion and to a large degree on CD4 þ effector T cell (T eff ) 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 T eff and T reg 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 þ T cells by combining ICOS agonism and T reg depletion. Cancer Res; 76(13); 3684-9. Ó2016 AACR.

A novel combination of chemotherapy and immunotherapy controls tumor growth in mice with a human immune system

“…In line with published results in murine models (41), we confirm here that blocking ICOS alone was not sufficient to impact tumor growth. However, a combination of chemotherapy and anti-ICOS mAb significantly impacted tumor growth in CD34-HuMice.…”

Ligand-Blocking and Membrane-Proximal Domain Targeting Anti-OX40 Antibodies Mediate Potent T Cell-Stimulatory and Anti-Tumor Activity

“…There was little change in population for intratumoral Foxp3À CD4+ Teff cells ( Figure 4D). Based on previous work showing that the observed anti-tumor activity of OX86 in the mIgG2a isotype is due to intratumoral Treg cell depletion via antibody-dependent cellular cytotoxicity (Bulliard et al, 2014;Metzger et al, 2016), we also measured Treg cell frequencies. However, there was little change in population for both intratumoral and spleen Foxp3+ CD4+ Treg cells ( Figure 4E; Figure S4).…”

Phenotype molding of T cells in colorectal cancer by single‐cell analysis

“…In multiple myeloma, CD38+ Tregs have been reported to be more immunosuppressive in vitro than CD38− Tregs . ICOS is a T‐cell coregulatory receptor that provides a costimulatory signal to T cells during antigen‐mediated activation . High level of ICOS is also indicative of the suppressive property of Treg .…”

“…34 ICOS is a T-cell coregulatory receptor that provides a costimulatory signal to T cells during antigen-mediated activation. 35 High level of ICOS is also indicative of the suppressive property of Treg. 36 A similar population was identified in a patient with clear cell renal cell carcinoma.…”