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

2016; Cell Press; Volume: 167; Issue: 2 Linguagem: Inglês

10.1016/j.cell.2016.08.069

1097-4172

Jianjun Gao, Lewis Z. Shi, Hao Zhao, Jianfeng Chen, Liangwen Xiong, Qiuming He, Tenghui Chen, Jason Roszik, Chantale Bernatchez, Scott E. Woodman, Pei-Ling Chen, Patrick Hwu, James P. Allison, P. Andrew Futreal, Jennifer A. Wargo, Padmanee Sharma,

CAR-T cell therapy research

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.