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

Cell | Oct 6, 2016

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.

Pubmed ID: 27667683 RIS Download

Mesh terms: Animals | Antibodies, Monoclonal | CTLA-4 Antigen | Cell Line, Tumor | Cytokines | Drug Resistance, Neoplasm | Gene Knockdown Techniques | Humans | Interferon-gamma | Ipilimumab | Melanoma | Melanoma, Experimental | Mice | Mice, Inbred C57BL | Receptors, Interferon | Skin Neoplasms | T-Lymphocytes

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Associated grants

  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NCI NIH HHS, Id: R01 CA163793
  • Agency: NCI NIH HHS, Id: L30 CA117817
  • Agency: NCI NIH HHS, Id: K12 CA088084
  • Agency: NCI NIH HHS, Id: K08 CA160692

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