Anti-CTLA4 activates intratumoral NK cells and combined with IL15/IL15R-alpha complexes enhances tumor control

Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors co-treated with GVAX, anti-CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcRs). Anti-CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Tregs). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous BrafV600EPten-/- melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T cell subsets, and anti-CTLA-4 treatment led to Fc/FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral NK cells. Similarly, in NSCLC and melanoma patient-derived tumor tissue Tregs had higher sCTLA-4 expression than other intratumoral T cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Cutaneous melanoma patients who benefited from Ipilimumab, a monoclonal antibody targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti-CTLA-4 plus IL15/IL15R-alpha complexes enhanced tumor control compared to either monotherapy.