Target the activin receptor 1c on CD4+ T cells to achieve anti-tumor therapeutic effects.

Abstract

Abstract Activin signaling molecules and their receptors have not been substantially studied in the context of the immune system and cancer. We show here that tumor-bearing mice had elevated Activins levels, which correlated directly with tumor burden. Likewise, cancer patients had elevated plasma Activins compared to healthy controls. Importantly, our in vitro studies suggested that Activins promoted differentiation of naive wild type CD4+ cells into induced FoxP3-expressing Tregs. Database and qRT-PCR analysis of sorted major immune cell subsets in mice revealed that Activin Receptor 1C (ActR1c) was uniquely expressed on Tregs. ActR2b, as paired to ActR1c, was found to be highly upregulated during iTreg differentiation. In humans, these receptors were expressed on CD4+ Foxp3− cells. Thus, while Activins may have many cellular targets, signaling through these receptors on CD4+ cells likely promotes Treg-mediated immunosuppression. In vivo B16 melanoma and MC38 colon tumor studies have demonstrated that mice lacking ActR1c were more resistant to cancer progression compared to wild type mice. This phenotype correlated with reduced expression of the FoxP3 transcription factor in CD4+ cells. The anti-tumor effect was T-cell dependent, as T cell-deficient mice reconstituted with naïve ActR1c knock out CD4+ cells had delayed tumor progression. In vitro, naïve CD4+ cells lacking ActR1c had a defect in their ability to gain FoxP3 expression when Activin A was present and when TGF-β was limited. Thus, blocking Activins signaling through this receptor is a promising and disease-specific strategy for preventing the accumulation of immunosuppressive iTregs in cancer. Supported by grants from NIH (R01AI137046)