Expression of IFNgR on tumor cells impact response to anti-CTLA-4 (TUM2P.1034)

Abstract

Abstract Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, Ipilimumab (BMS), has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of Ipilimumab for the treatment of metastatic melanoma. Our published data indicate that anti-CTLA-4 treatment resulted in marked increase of IFN-gamma (IFNg) production by CD4 T cells expressing inducible costimulator (ICOS). Studies in mice have demonstrated the importance of IFNg for effective anti-tumor responses. We hypothesized that tumor cell expression of IFNg-receptor (IFNg-R) would be necessary for tumor regression mediated by anti-CTLA-4. To test our hypothesis, we conducted both in vitro and in vivo experiments with tumor cell lines containing knockdown of IFNg-R. In the presence of IFNg, proliferation of tumor cells was inhibited; however, tumor cells lacking IFNgR were resistant to IFNg and were able to proliferate. In addition, mice inoculated with tumor cells lacking IFNgR were treated with anti-CTLA-4 and found to have impaired tumor rejection and higher mortality as compared to mice bearing tumor cells with intact IFNgR. Our data strongly suggest that intact IFNg-R expression and signaling on tumor cells is important for anti-CTLA-4-mediated anti-tumor responses. Our data point to a potential mechanistic pathway to explain why some patients may respond to therapy while others do not and we’re evaluating tumor samples from patients treated with anti-CTLA-4 to test this concept.