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Activin-A impedes the establishment of CD4+ T cell exhaustion and enhances anti-tumor immunity in the lung [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE183544 | GEO | 2021/09/10

REPOSITORIES: GEO

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Project description:Background: Despite current therapeutic treatments including surgery, chemotherapy, radiotherapy and recently immunotherapy, the mortality rate of lung cancer stays high. Regarding lung cancer, epigenetic modifications altering cell cycle, angiogenesis and programmed cancer cell death are therapeutic targets to combine with immunotherapy to improve treatment success. In a recent study, we uncovered a dual function of a molecule called QAPHA ((E)-3-(5-((2-cyanoquinolin-4-yl)(methyl)amino)-2-methoxyphenyl)-N-hydroxyacrylamide) as both a tubulin polymerization and HDAC inhibitors. Here, we investigate the impact of this novel dual inhibitor on the lung cancer immune response. Methods: To elucidate the mechanism of action of QAPHA, we conducted a chemical proteomics analysis. Using an in vivo mouse model of lung cancer (TC-1 tumor cells), we assessed the effects of QAPHA on tumor regression. Tumor infiltrating immune cells were characterize by flow cytometry. Results In this study, we first show that QAPHA can inhibit HDAC6, leading to upregulation of HSP90, cytochrome C and caspases, found by proteomic analysis. We also confirm that QAPHA induces immunogenic cell death (ICD) by upregulating HMGB1 in vitro and demonstrated its effectiveness as a vaccine in vivo. Remarkably, even at a low concentration (0.5mg/kg), QAPHA achieved complete tumor regression in approximately 60% of intratumorally treated mice, establishing a long-lasting anticancer immune response. Moreover, QAPHA treatment promoted infiltration of neutrophils in the treated mice, reflecting inflammatory cell death promoted. Very interestingly, we show that QAPHA is also able to upregulate MHC-II expression on TC-1 tumor cells in vitro and in vivo. This process participates to the recruitment of CD4+ NKG2D+ CRTAM+ Perforin+ T cells in tumor infiltrate, defined as cytotoxic CD4+ T cells (CD4+ CTL). Finally, we show that tumor regression is strongly correlated to MHC-II expression level on tumor cell and CD4+ CTL infiltrate. Conclusion Collectively, our findings shed light on the discovery of a new multi-target inhibitor able to induce ICD and MHC-II upregulation in TC-1 tumor cell. These two processes participate to enhance a specific CD4+ cytotoxic T cell-mediated anti-tumor response in vivo in our model of lung cancer. This breakthrough suggests the potential of QAPHA as a promising therapeutic agent for cancer treatment.

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Activin-A impedes the establishment of CD4+ T cell exhaustion and enhances anti-tumor immunity in the lung [RNA-seq]

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