Agonistic anti-ICOS antibodies promote unexpected elimination of tumor infiltrating effector T cells in a FcγR-independent manner

Abstract

Abstract Inducible T cell co-stimulator (ICOS) is a co-stimulatory receptor expressed on tumor infiltrating regulatory and effector T cells. ICOS potential role in cancer control is supported by the correlation between ipilimumab’s efficacy and the presence of CD4+ICOShi T cells in PBMC, as well as loss of tumor control in ICOS−/− and ICOSL−/− mice treated with anti CTLA-4. 37A10 is an anti ICOS agonistic mAb reactive to mouse and human ICOS, with a human IgG1 Fc region to promote depletion of regulatory T cells through antibody-dependent cellular cytotoxicity. We hypothesized a pure agonistic, non-depleting anti ICOS would promote co-stimulatory signals on activated T cells while avoiding depletion of activated ICOS+ T cells. Hence, we aimed to compare the efficacy in tumor control of two isotypes of 37A10. Both mIgG1 (non-depleting) and mIgG2a (depleting) isotypes failed to promote survival, as a monotherapy or in combination with anti PD-1 or anti CTLA-4. This was consistent with both isotypes promoting the elimination of activated T cells in an Fc-independent manner. Ablation of activated effector T cells with anti ICOS replicated loss of activated effector T cells upon in vivo blockade of ICOSL reflecting their ligand blocking activity. Moreover, both isotypes impaired the activity of anti CTLA-4, associated to effector T cell depletion, raising concerns regarding the use of anti ICOS mAbs as combination substrates in tumor immunotherapy. The data suggest that agonistic antibodies that block the natural ligand binding site and have weak in vivo agonism could result in unwanted negative responses in cancer. Future work should aim to identify antibodies with robust agonistic activity in vivo while allowing signaling induced by the natural ligand.