Loss of IFN-? Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy.

ABSTRACT: 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-?, which is a critical cytokine for host immune responses. However, the role of IFN-? 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-? pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-? receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-? signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-? related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.

SUBMITTER: Gao J 

PROVIDER: S-EPMC5088716 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature