Role of Activin-A signaling in melanoma

Cutaneous melanomas arise from transformed skin melanocytes. While accounting for only 1% of skin malignancies, melanoma is responsible for the majority of skin cancer-related deaths. Owing to lifestyle changes and increased exposure to sunlight, melanoma occurrence is on the rise in developed countries. Identification of the molecular mechanisms driving melanoma formation led to the development of new classes of therapeutics which revolutionized the standard of care. Among these, small molecule inhibitors targeting the MAPK pathway and immune checkpoint inhibitors resulted in unprecedented clinical success. Nevertheless, many patients still do not benefit from these therapies. Activin-A, a secreted ligand of the TGF-β superfamily, was recently found to be overexpressed in melanoma. However, whether Activin-A signaling promotes melanoma progression or therapy resistance is unknown. In this thesis, the contributions of autocrine and paracrine Activin-A signaling to melanoma growth are analyzed using lentiviral expression in melanoma cells of a constitutively active mutant type I Activin receptor (caALK4), of secreted Activin-A (gain-of-function), or of a ligand trap (loss-of-function). Paradoxically, while forced ALK4 signaling in melanoma grafts restored tumor suppression by inhibiting tumor cell survival and proliferation, transgenic Activin-A accelerated tumor growth. Conversely, expression of a ligand trap comprising the extracellular domain of Activin receptor IIB fused to human Fc (AIIB-Fc) slowed melanoma growth. Importantly, in immunodeficient Rag1-/- mice, effects of paracrine Activin-A gain and loss-of-function were abrogated, suggesting that Activin-A promotes melanoma progression by inhibiting the adaptive anti-tumor response. Flow cytometry analysis of tumor immune infiltrates combined with antibody-mediated cell depletion experiments confirmed that Activin-A promotes melanoma progression by inhibiting CD8+ tumor-infiltrating lymphocytes (TILs). Furthermore, inhibition of endogenous Activin-A sensitized a treatment-resistant melanoma model to immune checkpoint inhibition by anti-PD1 and anti-CTLA4 antibodies. Activin-A therefore emerges as a promising target to improve immunotherapy outcome in melanoma.