ABSTRACT
Activins, members of the TGF-beta superfamily, have been isolated and identified in the endocrine system, but have not been substantially investigated in the context of the immune system and endocrine-unrelated cancers. Here, we demonstrated that tumor-bearing mice had elevated systemic activin levels, which correlated directly with tumor burden. Likewise, cancer patients have elevated plasma activin levels compared to healthy controls. We observed that both tumor and immune cells could be sources of activins. Importantly, our in vitro studies suggest that activins promote differentiation of naïve CD4+ cells into Foxp3-expressing induced regulatory T cells (Tregs), particularly when TGF-beta was limited in the culture medium. Database and qRT-PCR analysis of sorted major immune cell subsets in mice revealed that activin receptor 1c (ActRIC) was uniquely expressed on Tregs and that both ActRIC and ActRIIB (activin receptor 2b) were highly upregulated during iTreg differentiation. ActRIC-deficient naïve CD4+ cells were found to be defective in iTreg generation both in vitro and in vivo. Treg suppression assays were also performed, and ActRIC deficiency did not change the function or stability of iTregs. Mice lacking ActRIC or mice treated with monoclonal anti-ActRIC antibody were more resistant to tumor progression than wild-type controls. This phenotype was correlated with reduced expression of Foxp3 in CD4+ cells in the tumor microenvironment. In light of the information presented above, blocking activin-ActRIC signaling is a promising and disease-specific strategy to impede the accumulation of immunosuppressive iTregs in cancer. Therefore, it is a potential candidate for cancer immunotherapy.
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Acknowledgments
The authors would like to acknowledge the generous time and expertise of the flow cytometry staff, Ada Tam, Richard L. Blosser, and Jessica Gucwa. Chirag Patel helped with methodology development and experimental design. We thank Dr. Suzanne L. Topalian, Tracee McMiller, and members of the Topalian Lab for processing and archiving the human plasma samples.
Disclosure statement
Y.Z., A.L., J.F., and D.P. are inventors of a licensed patent related to this work and are eligible to receive royalties. The terms of this arrangement have been reviewed and approved by Johns Hopkins University School of Medicine in accordance with its policy on objectivity in research.
Data availability statement
The authors confirm that the data supporting the findings of this study are available in the article and its supplementary materials. Raw data generated at the Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, are available from the corresponding author Y.Z. and D.P. on request.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2297503.