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Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy
Open accessAbstract
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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“Mutations in IFNGR1 and JAK, a component of the IFNγ signaling pathway, have been found in patients presenting resistance to checkpoint inhibitors (Gao et al., 2016; Zaretsky et al., 2016).”
From Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens (2018) · cites this paper as Gao et al., 2016
In the citing paper
“These findings are consistent with emerging clinical data correlating resistance to checkpoint inhibitors with mutations in the B2m and IFNγ pathways (Gao et al., 2016; Zaretsky et al., 2016), and with recent genome-wide CRISPR screening data (Patel et al., 2017).”
From Protein Barcodes Enable High-Dimensional Single-Cell CRISPR Screens (2018) · cites this paper as Gao et al., 2016
In the citing paper
“P. distasonis has been shown to enhance immune checkpoint inhibitor-mediated anticancer immunity by inducing the production of IFNγ+CD8+ T cells.53 54”
In the citing paper
“In addition, knockdown of IFNγ-receptor 1 led to impaired antitumor responses with anti-CTLA4 in a murine model of melanoma (159).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [159]
In the citing paper
“Interferon (IFN) signaling through the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway plays a prominent role in tumor immunity.”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Gao et al., 2016
In the citing paper
“Defects associated with this pathway and its downstream effectors have shown both negative and positive correlations with response to ICB, suggesting a dual role for this pathway in tumor immunity (Ayers et al., 2017; Gao et al., 2016).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Gao et al., 2016
In the citing paper
“Loss of IFN-ɤ signaling could induce resistance to anti-CTLA-4 treatment (95).”
From Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy (2020) · cites this paper as [95]
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“Together with other studies, the common features during immunotherapy resistance are B-catenin activation [44–46], PTEN loss [37,47], lack of response to IFNg [48,49], depletion of tumor-specific neo-antigen presentation [49,50], genome instability [51,52], cell-cycle dysregulation [53] and epigenetic modulations [38,…”
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“…this strategy will be effective in tumors that mutate or downregulate genes associated with antigen presentation [220] or interferon signaling pathways [221,222], and (3) whether efficient targets and drugs can be identified that selectively activate REs in cancer cells but not normal cells.”
BackgroundZhao, X., Liu, B., William, W. N., Tsanov, K. M., Ho, Y.-J., Barriga, F. M., Lim, R. J., Trifas, M., Khandekar, A., Du, Y., et al. (2024) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2024.12.020 · Cited by 19
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Sharma, A., Campbell, M. T., Yee, C., Goswami, S., & Sharma, P. (2019) · Elsevier eBooks · doi:10.1016/b978-0-7020-6896-6.00077-6 · Cited by 17
Self-citationThe Effects of Clonal Heterogeneity on Cancer Immunosurveillance
Dijkstra, K. K., Wu, Y., & Swanton, C. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061521-101910 · Cited by 16
Genetic and immune landscape evolution in MMR‐ deficient colorectal cancer
Challoner, B. R., Woolston, A., Lau, D. K., Buzzetti, M., Fong, C., Barber, L. J., Anandappa, G., Crux, R., Assiotis, I., Fenwick, K., et al. (2023) · The Journal of Pathology · doi:10.1002/path.6228 · Cited by 19
“Fifty-fi ve primary tumour regions, 15 lymph nodes, and one distant metastasis from 20 CRCs were sequenced with a panel of 194 genes (supplementary material, Table S1) that are recurrently mutated in MMRd or MMRp CRCs or implicated in IE and may confer CPI resistance [12,15,19,22 – 24].”
BackgroundMethodInfluentialGlutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells
Yuan, Z., Yu, T., Wang, X., Meng, K., Wang, T., Wang, B., Xi, Y., Wang, C., Zeng, C., Hu, S., et al. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107643 · Cited by 16
Interferon-driven Metabolic Reprogramming and Tumor Microenvironment Remodeling
Chang, T.-H., & Ho, P. (2025) · Immune Network · doi:10.4110/in.2025.25.e8 · Cited by 19
Next-Generation Sequencing to Guide Treatment of Advanced Melanoma
Griewank, K., & Schilling, B. (2017) · American Journal of Clinical Dermatology · doi:10.1007/s40257-017-0260-6 · Cited by 17
α-Selective Lysine Ligation and Application in Chemical Synthesis of Interferon Gamma
Dao, Y., Han, L., Wang, H., & Dong, S. (2019) · Organic Letters · doi:10.1021/acs.orglett.9b00980 · Cited by 16
Drug resistance in cancer immunotherapy: new strategies to improve checkpoint inhibitor therapies
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“, mutations of MAPK pathway [35], loss of PTEN [36] with an increase of PI3K [37,38], expression of WNT/β-catenin [39], altered IFN-α pathway [40], EGFR mutations [41], MYC overexpression [42]), alterations of PDJ amplicon on chromosome 9, which codes for PD-L1/2 and JAK2, and alterations of a gene set called IPRES [4…”
BackgroundUltrasound and microbubble-mediated drug delivery and immunotherapy
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“For example, an increased frequency of IFN-γ pathway gene mutations in tumors of melanoma patients that did not respond to the anti-CTLA-4 antibody ipilimumab has been shown([37,138]).”
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Immunotherapy in GI Cancers: Lessons from Key Trials and Future Clinical Applications
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“Interferon-γ has a twofold function in inducing PD-L1 upregulation that facilitates immune escape [102–104] and enhances chemokine generation and pro-apoptotic pathways for immune cell invasion and cell death in tumor cells [103,105,106].”
Cancer vaccines: Discovery, development, and challenges for clinical translation
Zhang, Z., Yao, S., Wang, Y., Luo, K., Amiji, M. M., & Anderson, K. C. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123615 · Cited by 15
Ms4a7 expression in cDC1s determines cross-presentation and antitumor immunity
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The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas
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“Additionally, driver mutations of the JAK-STAT pathway may contribute to tumor progression during immunotherapy (32, 33).”
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Understanding genetic determinants of resistance to immune checkpoint blockers
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Post‐transcriptional control of T‐cell cytokine production: Implications for cancer therapy
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STUB1 is an intracellular checkpoint for interferon gamma sensing
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Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma
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Hossain, S. M., Carpenter, C., & Eccles, M. R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137252 · Cited by 15
“For instance, driver mutations and CNAs can activate or suppress pathways that interact with tumour–immune signalling channels [43] such as the IFN-γ signalling pathway, resulting in acquired resistance to anti-PD1 therapy in metastatic melanoma [44].”
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Metadata
- Authors
- Gao, J., Shi, L. Z., Zhao, H., Chen, J., Xiong, L., He, Q., Chen, T., Roszik, J., Bernatchez, C., Woodman, S. E., Chen, P.-L., Hwu, P., Allison, J. P., Futreal, A., Wargo, J. A., & Sharma, P.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Sharma, Padmanee
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-10
- Volume
- 167
- Issue
- 2
- Pages
- 397-404.e9
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5088716
- OpenAlex
- W2522313999
- Cited by
- 1,300
- References
- 41
- Citations by year
- 2026: 83 · 2025: 107 · 2024: 128 · 2023: 158 · 2022: 137 · 2021: 174 · 2020: 162 · 2019: 128 · 2018: 121 · 2017: 89 · 2016: 8
- FWCI
- 62.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (L30 CA117817, R01CA163793, K08CA160692, P30CA016672, K12CA088084)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- interferon-gamma signaling, IFNGR1, CTLA-4 blockade, ipilimumab, metastatic melanoma, immune checkpoint therapy, tumor rejection, prognostic factors, T cell response
- MeSH terms
- Ipilimumab, Interferon gamma Receptor, Animals, Antibodies, Monoclonal, Humans, Interferon-gamma, Melanoma, Melanoma, Experimental, Mice, Inbred C57BL, Skin Neoplasms, T-Lymphocytes, Cytokines, Receptors, Interferon, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, Gene Knockdown Techniques, CTLA-4 Antigen
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