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

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.

Different Immunoregulation Roles of Activin A Compared With TGF-β

“…On the one hand, endogenous activin A may suppress anti-tumor immunity by inducing differentiation of Tr1, deactivating innate immune cells or inhibiting cytokine secretion from CD4 + T cells. On the other hand, surprisingly, adoptive transfer of exogenous activin A-treated DCs or CD4 + T cells prevents tumor cells from growing, which provides a brand new insight on functions of TGF-β superfamily ( 36 , 58 ).…”

“…In contrast, Morianos, I. et al. provided evidence which might uncover activin A’s role as an anti-tumor factor ( 58 ). Treatment of OVA-expressing Lewis Lung Carcinoma mice with activin A attenuated tumor progression and heightened the ratio of tumor-infiltrating effectors to regulatory CD4 + T cells ( 58 ).…”

“…provided evidence which might uncover activin A’s role as an anti-tumor factor ( 58 ). Treatment of OVA-expressing Lewis Lung Carcinoma mice with activin A attenuated tumor progression and heightened the ratio of tumor-infiltrating effectors to regulatory CD4 + T cells ( 58 ). The expression of immune checkpoints including programmed cell death protein 1(PD-1), lymphocyte-activation gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on tumor-infiltrating CD4 + T cells was reduced as well ( 58 ).…”

“…Treatment of OVA-expressing Lewis Lung Carcinoma mice with activin A attenuated tumor progression and heightened the ratio of tumor-infiltrating effectors to regulatory CD4 + T cells ( 58 ). The expression of immune checkpoints including programmed cell death protein 1(PD-1), lymphocyte-activation gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on tumor-infiltrating CD4 + T cells was reduced as well ( 58 ). Adoptive transferring of activin A-treated lung tumor-infiltrating CD4 + T cells into CD4 (-/-)-tumor-bearing mice could suppress tumor progression without CD4 + T cell exhaustion ( 58 ).. All of these results indicated that activin A might be a novel therapeutic molecule for lung cancer.…”

Potential targeted therapy based on deep insight into the relationship between the pulmonary microbiota and immune regulation in lung fibrosis

“…Recently, a study found that the release of neutrophil elastase is an essential link in cystic pulmonary fibrosis. Because neutrophil elastase could destroy the pulmonary capillary barrier and activate the B cell immune response ( 4 , 42 ), the abnormal pulmonary microbiota can lead to Staphylococcus becoming an opportunistic pathogen ( 43 ). Staphylococcal protein A (SPA) is a surface protein of staphylococcal, which combines with mucin of the cell wall.…”