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

Jianjun Gao; Lewis Zhichang 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; Andrew Futreal; Jennifer A. Wargo; Padmanee Sharma

doi:10.1016/j.cell.2016.08.069

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

Jianjun Gao, Lewis Zhichang 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, Andrew Futreal, Jennifer A. Wargo, Padmanee Sharma

Research output: Contribution to journal › Article › peer-review

908 Scopus citations

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.

Original language	English (US)
Pages (from-to)	397-404.e9
Journal	Cell
Volume	167
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2016.08.069
State	Published - Oct 6 2016

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Advanced Technology Genomics Core
Clinical and Translational Research Center
Functional Genomics Core
Research Animal Support Facility
Tissue Biospecimen and Pathology Resource
Cytogenetics and Cell Authentication Core
Clinical Trials Office

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10.1016/j.cell.2016.08.069

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

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",

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

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doi = "10.1016/j.cell.2016.08.069",

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T1 - Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy

AU - Gao, Jianjun

AU - Shi, Lewis Zhichang

AU - Zhao, Hao

AU - Chen, Jianfeng

AU - Xiong, Liangwen

AU - He, Qiuming

AU - Chen, Tenghui

AU - Roszik, Jason

AU - Bernatchez, Chantale

AU - Woodman, Scott E.

AU - Chen, Pei Ling

AU - Hwu, Patrick

AU - Allison, James P.

AU - Futreal, Andrew

AU - Wargo, Jennifer A.

AU - Sharma, Padmanee

PY - 2016/10/6

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N2 - 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.

AB - 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.

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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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