[PDF][PDF] Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy

J Gao, LZ Shi, H Zhao, J Chen, L Xiong, Q He, T Chen… - Cell, 2016 - cell.com
J Gao, LZ Shi, H Zhao, J Chen, L Xiong, Q He, T Chen, J Roszik, C Bernatchez
Cell, 2016cell.com
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 …
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.
cell.com