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Cell. 2016 Oct 6;167(2):397-404.e9. doi: 10.1016/j.cell.2016.08.069. Epub 2016 Sep 22.

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

Author information

1
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: padsharma@mdanderson.org.

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-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.

KEYWORDS:

IFN-γ signaling; Melanoma; anti-CTLA-4; copy-number alteration; ipilimumab; primary resistance

PMID:
27667683
PMCID:
PMC5088716
DOI:
10.1016/j.cell.2016.08.069
[Indexed for MEDLINE]
Free PMC Article

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