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

By Jianjun Gao, L. Shi, Hao Zhao, Jianfeng Chen, Liangwen Xiong, Qiu-ming He, Tenghui Chen, J. Roszik, C. Bernatchez, S. Woodman and 6 more. Cell, 2016

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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.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/f19fad08536e8b9f2a04249638a2f8f29324db4d

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Citations in the corpus

Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer (2017, methodology): “Since genetic defects in interferon pathway related genes have been associated with primary and acquired resistance to ICIs, we compiled a list of 101 IFN pathway-related genes (33) and queried them for mutations and copy number alterations in our cohort (excluding the hypermutator, case 17, that wa”
Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, neutral): “In another study, melanoma patients who failed to respond to antiCTLA4 were found to have copy number alterations in IFN pathway genes (Gao et al., 2016).”
Primary resistance to PD-1 blockade mediated by JAK1/2 mutations (2016, background): “In primary resistance to checkpoint blockade therapy with the anti–CTLA-4 antibody ipilimumab, there is a higher frequency of mutations in the several molecules involved in the interferon signaling pathway (18).”
Defining T cell states associated with response to checkpoint immunotherapy in melanoma (2018, neutral): “…available for 20 patient tumor and normal pairs, identified four tumors with somatic mutations in B2M, JAK1, STAT1, and IFNGR1 (Table S1), recently associated with primary or acquired resistance to checkpoint therapy in melanoma (Gao et al., 2016; Sade-Feldman et al., 2017; Zaretsky et al., 2016).”
Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion (2018, background): “In fact, 75% of metastatic melanoma patients were non-responders to anti-CTLA-4 therapy, and this was associated with genomic defects of IFN-γ signaling genes on tumors (241).”
Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, background): “, 2015) and clinical reports (Gao et al., 2016; George et al., 2017; Zaretsky et al., 2016) have described associations between individual altered genes and response or resistance to immune checkpoint blockade (Table S4).”