Prolactin enhances T regulatory cell promotion of breast cancer through the long form prolactin receptor

Translational Oncology

Mrinal Ghosh¹  Srividya Swaminathan²  Mary Y. Lorenson²  Lorena Rivera³  Ameae M. Walker³  Kuan-Hui Ethan Chen³  Samuel Lin³  Anil Kumar³ 

[1] Corresponding authors.;Department of Systems Biology, Beckman Research Institute, City of Hope, Duarte, CA 91010, United States;Division of Biomedical Sciences, University of California, Riverside, CA 92521, United States;

关键词: Prolactin receptor knockdown;    Prolactin;    Tumor Treg recruitment;    Epithelial to mesenchymal transition;    TGF-β1;    IL-10;   

DOI  :  

来源: DOAJ

【 摘 要 】

Previous work has shown systemic knockdown of the long form prolactin receptor (LFPRLR) in vivo markedly reduced metastasis in mouse models of breast cancer, but whether this translated to prolonged survival was unknown. Here we show that LFPRLR knockdown in the highly metastatic, immunocompetent 4T1 model prolonged survival and reduced recruitment of T regulatory cells (Tregs) to the tumor through effects on the production of CCL17. For the Tregs still recruited to the primary tumor, LFPRLR knockdown both directly and indirectly reduced their ability to promote tumor parenchymal epithelial to mesenchymal transition. Importantly, effects of prolactin on expression of mesenchymal genes by the tumor parenchyma were very different in the absence and presence of Tregs. While systemic knockdown of the LFPRLR downregulated transcripts important for immune synapse function in the remaining tumor Tregs, splenic Tregs seemed unaffected by LFPRLR knockdown, as demonstrated by their continued ability to suppress anti-CD3/CD28-stimulated effector cell proliferation at 1–5 months. These results demonstrate that knockdown of the LFPRLR achieves intra-tumor immunotherapeutic effects and suggest this occurs with reduced likelihood of peripheral inflammatory/autoimmune sequelae.

【 授权许可】

Unknown