No abstract

SUMMARY Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

CrossMap is written in Python and C. Source code and a comprehensive user's manual are freely available at: http://crossmap.sourceforge.net/.

To date, anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) monotherapy has not demonstrated significant clinical benefit in patients with prostate cancer. To identify additional immune inhibitory pathways in the prostate tumor microenvironment, we evaluated untreated and ipilimumab-treated tumors from patients on a pre-surgical clinical trial. PD-L1 and VISTA inhibitory molecules increased on independent subsets of macrophages. Our data suggest that VISTA is another compensatory inhibitory pathway in prostate tumors after ipilimumab therapy.