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Inhibition of anti-tumor immunity by melanoma cell-derived Activin-A depends on STING (scRNA-Seq)

ABSTRACT: The transforming growth factor-β (TGF-ꞵ) family member activin A (hereafter Activin-A) is overexpressed in many cancer types, often correlating with cancer-associated cachexia and poor prognosis. Activin-A secretion by melanoma cells indirectly impedes CD8+ T cell-mediated anti-tumor immunity and promotes resistance to immunotherapies, even though Activin-A can be proinflammatory in other contexts. To identify underlying mechanisms, we here analyzed the effect of Activin-A on syngeneic grafts of Braf mutant YUMM3.3 mouse melanoma cells and on their microenvironment using single-cell RNA sequencing. We found that the Activin-A-induced immune evasion was accompanied by a proinflammatory interferon signature across multiple cell types, and that the associated increase in tumor growth depended at least in part on pernicious STING activity within the melanoma cells. Besides corroborating a role for proinflammatory signals in facilitating immune evasion, our results suggest that STING holds considerable potential as a therapeutic target to mitigate tumor-promoting Activin-A signaling at least in melanoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE247228 | GEO | 2024/02/07

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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Inhibition of anti-tumor immunity by melanoma cell-derived Activin-A depends on STING (scRNA-Seq)

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