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Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy.

ABSTRACT: Interferon-gamma (IFN-γ) has been identified as a crucial factor in determining the responsiveness to immunotherapy. Produced primarily by natural killer (NK) and T cells, IFN-γ promotes activation, maturation, proliferation, cytokine expression, and effector function in immune cells, while simultaneously inducing antigen presentation, growth arrest, and apoptosis in tumor cells. However, tumor cells can hijack the IFN-γ signaling pathway to mount IFN-γ resistance: rather than increasing antigenicity and succumbing to death, tumor cells acquire stemness characteristics and express immunosuppressive molecules to defend against antitumor immunity. In this review, we summarize the potential mechanisms of IFN-γ resistance occurring at two critical stages: disrupted signal transduction along the IFNG/IFNGR/JAK/STAT pathway, or preferential expression of specific interferon-stimulated genes (ISGs). Elucidating the molecular mechanisms through which tumor cells develop IFN-γ resistance help identify promising therapeutic targets to improve immunotherapy, with broad application value in conjugation with targeted, antibody or cellular therapies.

SUBMITTER: Han J

PROVIDER: S-EPMC10233742 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy.

Han Jiashu J Wu Mengwei M Liu Ziwen Z

Frontiers in immunology 20230518

Interferon-gamma (IFN-γ) has been identified as a crucial factor in determining the responsiveness to immunotherapy. Produced primarily by natural killer (NK) and T cells, IFN-γ promotes activation, maturation, proliferation, cytokine expression, and effector function in immune cells, while simultaneously inducing antigen presentation, growth arrest, and apoptosis in tumor cells. However, tumor cells can hijack the IFN-γ signaling pathway to mount IFN-γ resistance: rather than increasing antigen ...[more]

PMID: 37275859

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Project description:BackgroundUnderstanding the role and potential therapeutic targeting of tumor-associated macrophages (TAMs) is crucial to developing new biomarkers and therapeutic strategies for cancer immunotherapies. The epigenetic reader SP140 has emerged as a master regulator of macrophage transcriptional programs; however, its role in the signaling of TAMs and response to immunotherapy has not been investigated.MethodsWe evaluated the correlation between SP140 expression in head and neck squamous cell carcinoma (HNSCC) TAMs and clinical outcomes. We also used complementary bioinformatics and experimental approaches to study the association of SP140 expression with tumor mutation burden, patient survival, immunogenic signature of tumors, and signaling of TAMs. SP140 overexpression or knockdown was implemented to identify the role of SP140 in downstream signaling and production of inflammatory cytokine and chemokines. Chromatin immunoprecipitation and analysis of assay of transposase accessible chromatin sequencing data were used to demonstrate the direct binding of SP140 on the promoters of STAT1. Finally, correlation of SP140 with immune cell infiltrates and response to immune-checkpoint blockade in independent cohorts of HNSCC, metastatic melanoma, and melanoma was assessed.ResultsWe found that SP140 is highly expressed in TAMs across many cancer types, including HNSCCs. Interestingly, higher expression of SP140 in the tumors was associated with higher tumor mutation burden, improved survival, and a favorable response to immunotherapy. Tumors with high SP140 expression showed enrichment of inflammatory response and interferon-gamma (IFN-γ) pathways in both pan-cancer analysis and HNSCC-specific analysis. Mechanistically, SP140 negatively regulates transcription and phosphorylation of STAT1 and induces IFN-γ signaling. Activating SP140 in macrophages and TAMs induced the proinflammatory macrophage phenotype, increased the antitumor activity of macrophages, and increased the production of IFN-γ and antitumor cytokines and chemokines including interleukin-12 and CXCL10. SP140 expression provided higher sensitivity and specificity to predict antiprogrammed cell death protein 1 immunotherapy response compared with programmed death-ligand 1 in HNSCCs and lung cancer. In metastatic melanoma, higher levels of SP140 were associated with a durable response to immunotherapy, higher immune score estimates, high infiltrations of CD8+ T cells, and inflammatory TAMs.ConclusionsOur findings suggest that SP140 could serve as both a therapeutic target and a biomarker to identify immunotherapy responders.

Project description:T cell large granular lymphocyte leukemia (T-LGLL) is a rare incurable disease that is characterized by defective apoptosis of cytotoxic CD8+ T cells. Chronic activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway is a hallmark of T-LGLL. One manifestation is the constitutive phosphorylation of tyrosine 701 of STAT1 (p-STAT1). T-LGLL patients also exhibit elevated serum levels of the STAT1 activator, interferon-γ (IFN-γ), thus contributing to an inflammatory environment. In normal cells, IFN-γ production is tightly controlled through induction of IFN-γ negative regulators. However, in T-LGLL, IFN-γ signaling lacks this negative feedback mechanism as evidenced by excessive IFN-γ production and decreased levels of suppressors of cytokine signaling 1 (SOCS1), a negative regulator of IFN-γ. Here we characterize the IFN-γ-STAT1 pathway in TL-1 cells, a cell line model of T-LGLL. TL-1 cells exhibited lower IFN-γ receptor protein and mRNA expression compared to an IFN-γ responsive cell line. Furthermore, IFN-γ treatment did not induce JAK2 or STAT1 activation or transcription of IFN-γ-inducible gene targets. However, IFN-β induced p-STAT1 and subsequent STAT1 gene transcription, demonstrating a specific IFN-γ signaling defect in TL-1 cells. We utilized siRNA targeting of STAT1, STAT3, and STAT5b to probe their role in IL-2-mediated IFN-γ regulation. These studies identified STAT5b as a positive regulator of IFN-γ production. We also characterized the relationship between STAT1, STAT3, and STAT5b proteins. Surprisingly, p-STAT1 was positively correlated with STAT3 levels while STAT5b suppressed the activation of both STAT1 and STAT3. Taken together, these results suggest that the dysregulation of the IFN-γ-STAT1 signaling pathway in TL-1 cells likely results from low levels of the IFN-γ receptor. The resulting inability to induce negative feedback regulators explains the observed elevated IL-2 driven IFN-γ production. Future work will elucidate the best way to target this pathway, with the ultimate goal to find a better therapeutic for T-LGLL.

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Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy.

Publications

Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy.

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