Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy.
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.
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jianjun
J
Gao
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Lewis Zhichang
LZ
Shi
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Hao
H
Zhao
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jianfeng
J
Chen
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Liangwen
L
Xiong
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Qiuming
Q
He
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Tenghui
T
Chen
Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jason
J
Roszik
Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Chantale
C
Bernatchez
Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Scott E
SE
Woodman
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Pei-Ling
PL
Chen
Department of Melanoma Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Patrick
P
Hwu
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
James P
JP
Allison
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Andrew
A
Futreal
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.
Jennifer A
JA
Wargo
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.
Padmanee
P
Sharma
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics*; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D017471:Receptors, Interferon / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D016207:Cytokines; D007371:Interferon-gamma; D000074324:Ipilimumab; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C556706:CTLA4 protein, human
IFN-γ signaling; Melanoma; anti-CTLA-4; copy-number alteration; ipilimumab; primary resistance
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