Abstract 2361: Progesterone receptor promotes immunosuppressive microenvironment in the mammary gland

Why are some early neoplastic lesions identified through immunosurveillance and subsequently destroyed, whereas other tumors evade this clearance step and progress to clinically-relevant tumors? The cancer immunoediting hypothesis highlights that the innate and adaptive immune responses work together to “flag” early neoplastic lesions for immune-mediated elimination. An early mediator of this “elimination” process is activation of type I interferon signaling. Thus, suppression of type I interferon signaling may help developing tumors evade the critical early steps of immune recognition and clearance. Preliminary data from our lab suggest that progesterone, working through the progesterone receptor (PR), may be a key player in tumor immune evasion through downregulation of interferon signaling. In breast cancer cells, we have shown that presence/activation of PR can attenuate interferon-signaling at multiple steps within the signaling cascade: decreased STAT1 phosphorylation, decreased STAT1/STAT2/IRF9 transcriptional complex formation (called ISGF3, required for interferon-alpha signaling), decreased recruitment of ISGF3 to ISG promoter sequences, and decreased transcriptional activation of interferon-stimulated genes (ISG, end point of interferon signaling). These data suggest a concerted effort aimed at reducing interferon-signaling through activation of PR. These data translate to the immune microenvironment in the murine mammary gland. In mice treated with progesterone for 21 days, we see immunosuppressive changes in the mammary gland: increased T-regulatory cells (immunosuppressive), decreased frequency of antigen-presenting cells (decreased ability to present potential tumor-associated antigens to CD8 T-cells), and a decrease in MHC class I presentation in non-lymphoid cells (decreased ability for epithelial cells to present potential tumor-associated antigens). We observe similar phenotypes in mice with transgenic overexpression of PR. These changes in the immune system suggest that PR can promote immunosuppressive changes in the mammary gland. Moreover, 80% of these mice in a multiparous cohort develop mammary gland tumors. Therefore, early changes in the immune microenvironment in the mammary gland may translate to the development of mammary gland tumors in PR transgenic mice. Cumulatively, these data suggest a mechanism through which PR aids early breast cancer lesions in escaping immune surveillance. These data have significant implications for the use of progesterone-containing hormone replacement therapy, as well as underscore the importance of studying anti-progestins as novel chemo-preventative agents for breast cancer. Citation Format: Merit Goodman, Gloria Trinca, Katherine Walter, Katelin Gibson, Prabhakar Chalise, Mary Markiewicz, Christy R. Hagan. Progesterone receptor promotes immunosuppressive microenvironment in the mammary gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2361.