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TET3 Promotes Tumor Immune Evasion Through Negative Regulation of Type I Interferon Signaling [RNA-Seq]

ABSTRACT: The Ten-eleven translocation (TET) family genes, which encode 5-methylcytosine (5mC) dioxygenases, have been described as tumor suppressors or oncogenes in various cancers. However, the functional role of TET3 in cancer immunity and the underlying molecular mechanisms remain incompletely understood. Here, we reported that TET3 restrains the innate immune response in MCF7 and B16F10 cells. Mechanistically, TET3 does not influence the generation of endogenous dsRNA but represses the expression of major dsRNA sensor genes (i.e., MDA5 and RIG-I) as well as the activation of JAK-STAT1 pathway. Importantly, depletion of Tet3 in B16F10 melanoma cells significantly curbed the synergistic tumor growth, accompanied with increased proportion of tumor-infiltrating CD4+ T cells, CD8+ T cells and dendritic cells. Analysis of the TCGA data also revealed elevated expression of TET3 in most types of cancer. Notably, elevated TET3 expression levels were inversely associated with overall survival rate and exhibited a negative correlation with tumor-infiltrating cytotoxic CD8+ T cells. Taken together, our findings identify TET3 as a negative regulator of type I interferon signaling, suggesting that TET3 may be a new target of anti-tumor immunity and immunotherapy.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE300460 | GEO | 2026/06/26

REPOSITORIES: GEO

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Project description:Background: Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. Methods: To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. Results: Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. Conclusions: In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.

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TET3 Promotes Tumor Immune Evasion Through Negative Regulation of Type I Interferon Signaling [RNA-Seq]

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