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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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“Studies have shown that IFN-γ could induce apoptosis or scorch death of cancer cells through IFN-γ receptors on the surface of cancer cells [55,56].”
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“IFN-g illustrates the dual role of immune regulation, as it promotes antitumor immunity by upregulating MHC I upregulation while simultaneously facilitating immune escape through the expression of PD-L1 and the recruitment of regulatory T cells (Tregs) (142, 143).”
Mogat1 drives metabolic adaptations to evade immune surveillance
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“While genome-wide genetic perturbation screens (e.g., CRISPR-Cas9) provide valuable insights into gene function 4 – 7 , particularly in vitro or under simpli fi ed in vivo conditions, they may not fully capture the adaptive changes occurring during tumor progression within a complex, evolving TME.”
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“Indeed, a past study confirmed that IFIT2 is significantly up-expressed in patients who are not sensitive to anti-CTLA-4 therapy in metastatic melanoma [41], suggesting that the IFIT family may be useful for predicting the efficacy of immune checkpoint therapy.”
BackgroundThe future of targeting cytotoxic T-lymphocyte-associated protein-4: Is there a role?
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“Furthermore, defects in the IFN response pathway, which regulates MHC-I levels, have also been correlated with resistance to checkpoint immunotherapy (23).”
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“For example, mutations in the JAK/STAT pathway abrogate responsiveness to IFNγ signaling and reduce neoantigen presentation, leading to a lack of responsiveness to ICI [40,41].”
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“Moreover, IFN-g activity on stroma cells may drive more inflammation given the local conditions to predispose the expansion of cancer (44).”
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ANGPTL2 ‐mediated epigenetic repression of MHC‐I in tumor cells accelerates tumor immune evasion
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“…that defects in the antigen presentation machinery and IFN c signaling contribute to acquired resistance to immune checkpoint inhibitors (ICIs) [8,37 – 39], we used a TGCA dataset [28] (Table S7) to assess an association between ANGPTL2 mRNA levels and overall survival after treatment with…”
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“IFN-gamma is known to stimulate the expression of PD-L1 in tumor cells through the activation of the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) signaling pathway [26].”
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“Somatic loss of function mutations and copy number loss of genes in the IFN γ pathway occur in melanomas resistant to ICB 55,56 , supporting that tumourintrinsic IFN γ signalling is essential for ICB treatment ef fi cacy.”
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Self-citationLycopene and Tomato Sauce Improve Hepatic and Cardiac Cell Biomarkers in Rats
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Immune Escape in Prostate Cancer
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“Interestingly, IRF1 is frequently deleted in patients that do not respond to CTLA4 inhibition.(38) Furthermore, IRF1 is a strong transcriptional activator of the MHC class I antigen presentation complex (Figure S5E), which plays a critical role in anti-tumor immunity by presenting neo-epitopes and stimulating T cell-m…”
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Cancer Cell Resistance to IFNγ Can Occur via Enhanced Double-Strand Break Repair Pathway Activity
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Clinical features of patients with MTAP-deleted bladder cancer.
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“Although ICIs have transformed treatment regimens for a variety of cancers (4,18,19,40), including NSCLC, not all patients respond to immunotherapy in the same way (10,26,41-45).”
STING signalling compensates for low tumour mutation burden to drive anti-tumour immunity
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Self-citationA consensus on immunotherapy from the 2017 Chinese Lung Cancer Summit expert panel
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Pharmacological Treatments Available for Immune-Checkpoint-Inhibitor-Induced Colitis
Ohwada, S., Ishigami, K., Akutsu, N., & Nakase, H. (2022) · Biomedicines · doi:10.3390/biomedicines10061334 · Cited by 11
“Tumors with deletions in the IFN-γ pathway gene do not benefit from anti-CTLA-4 therapy [40].”
BackgroundImmune-based cancer therapies: mechanistic insights, clinical progress, and future directions
Devaraji, M., & Cheriyan, B. V. (2025) · Journal of the Egyptian National Cancer Institute · doi:10.1186/s43046-025-00319-6 · Cited by 16
AARS1-mediated lactylation of STAT1 drives immune evasion
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“Many clinical reports have associated acquired resistance to ICB with loss of IFN γ response by tumour cells via signalling pathway mutations 16 – 18 .”
Ulcerated melanoma: Systems biology evidence of inflammatory imbalance towards pro‐tumourigenicity
Davies, J., Muralidhar, S., Randerson‐Moor, J. A., Harland, M., O'Shea, S. J., Diaz, J. M. S., Walker, C., Nsengimana, J., Laye, J. P., Mell, T., et al. (2021) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.13023 · Cited by 10
“The baits included 164 melanoma- associated genes, 245 known to be associated with other solid cancers, common melanoma promoter mutations, and 101 genes from the interferon signalling pathway (Gao et al., 2016) (Supplementary Excel File S1).”
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An HNSCC syngeneic mouse model for tumor immunology research and preclinical evaluation
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“The IFN‐γ pathway of tumor cells is indispensable for the antitumor function of immune cells (29).”
BackgroundDiscovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues
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Intestinal Bacteria Encapsulated by Biomaterials Enhance Immunotherapy
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“and improved overall survival (OS) by CTLA-4 blockade therapy,(4) there are still many patients (~80%) who do not respond,(4) possibly attributed to a lack of preexisting immunity.(5,6) Therefore, combination regimens that can initiate”
Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies
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Self-citationMechanism of resistance to immune checkpoint inhibitors
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“Significantly high frequency of mutations in the IFN-γ pathway was also seen in patients who were non-responders to ipilimumab compared to patients who responded to therapy([46]).”
Stachura, P., Liu, W., Xu, H. C., Wlodarczyk, A., Stencel, O., Pandey, P., Vogt, M., Bhatia, S., Picard, D. J., Remke, M., et al. (2023) · Molecular Cancer · doi:10.1186/s12943-023-01833-8 · Cited by 9
“Furthermore, as a means of primary and acquired resistance, many tumors inactivate interferon signaling [66].”
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“Mechanisms of resistance or non-responsiveness to ICI remain poorly understood, but evidence suggests multifactorial causes, including tumor mutational burden [ 17], PD-L1 expression level [18], interferon-γ signaling pathways [19], and inactivation of antigen presentation [20].”
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“These differences in tumor outgrowth might be a result of decreased IFNγ pathway gene expression (e.g. MHC-I and PD-L1), which is a well-known mechanism for immunotherapy resistance and decreased tumor outgrowth [26, 27].”
BackgroundResultMolecular Susceptibility and Treatment Challenges in Melanoma
Shenoy, P. V., Nag, R., Kolathur, K. K., Malik, Y., Varanasi, S. M., Angom, R. S., & Mukhopadhyay, D. (2024) · Cells · doi:10.3390/cells13161383 · Cited by 12
“This indicates that a loss of IFN-γ signaling in tumor cells may promote resistance to immune checkpoint therapies [177,178].”
BackgroundTriggering immunogenic death of cancer cells by nanoparticles overcomes immunotherapy resistance
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“Mutations linked to MHC regulation and IFNγ signaling were determined using experimentally validated gene list 25,26 .”
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“Indeed, the attenuation of intra-tumoral IFN signaling has been linked to immunosuppression in hypoxic tumors [51] and primary resistance to anti-CTLA-4 therapy in melanoma patients [52].”
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Transcriptome and genome evolution during HER2-amplified breast neoplasia
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“The main mechanism of resistance to CTLA-4 blockade involves the lack of the genes for response to interferon gamma by tumor cells [228].”
BackgroundPrimary Melanoma miRNA Trafficking Induces Lymphangiogenesis
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A new approach to overcoming resistance to immunotherapy: nanotechnology
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Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma
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“Studies have indicated that impairments in the IFN-γ signal pathway in melanoma could also lead to a reduced response to anti-CTLA-4 therapy [74].”
BackgroundZakharia, Y., Singer, E. A., Acharyya, S., Garje, R., Joshi, M., Peace, D. J., Baladandayuthapani, V., Majumdar, A., Xiong, L., Lalancette, C., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-45216-z · Cited by 11
“This is of interest given the involvement of IFN γ in host-tumor interactions 22 and because loss of the IFN γ signaling pathway impairs T-cellresponses,permitstumor growth 23 and could bea mechanismof primary resistance to CPI 24 .”
BackgroundSelf-citation
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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