Targeting the Progesterone Receptor as a Novel Means to Increase Efficacy of Immune Checkpoint Inhibitors in Hormone Receptor Positive Breast Cancer - ABSTRACT Approximately 75% of all breast cancers (BC) are classified as hormone receptor positive (HR+), the majority expressing both Estrogen and Progesterone Receptors (ER/PR). Although several classes of anti-estrogen endocrine therapies exist for these cancers, ~30% of women with ER+ breast cancer develop resistance and die from metastatic disease. Thus, new therapies are desperately needed for HR+ cancers, which constitute the majority of deaths from BC. While multiple therapies target ER and ER-signaling pathways, therapies targeting PR have not yet been employed, as its role in BC remains unclear. Our recent studies have revealed a significant immune modulatory role for PR in BC. Specifically, our early studies demonstrated a clear role for PR in suppressing cell intrinsic interferon responses through STAT1/2 inhibition. Recently, using transgenic PR models and orthotopic mouse PR+ BC lines, we demonstrated that PR expression results in enhanced tumor development and growth, which is dependent upon adaptive anti-tumor immunity, and altered immune infiltration into the mammary tumor microenvironment. These findings are congruent with clinical observations that HR+ BC have a striking reduction of tumor infiltrating lymphocytes in comparison to other BCs and are less responsive to immune checkpoint inhibitors (ICIs), such as anti-PD-L1 therapy. Thus, our past and current studies strongly suggest that HR+ BC immunosuppression is mediated by tumor cell PR expression and immunomodulation of the local tumor microenvironment (TME). We hypothesize that therapeutic targeting of PR will fundamentally alter the immunosuppressive mammary microenvironment and afford more robust responses of HR+ BC following treatment with ICIs. We will test this hypothesis in the following Aims: 1) Determine the anti-tumor utility of anti-progestins with anti-PD-L1 ICI as a means to elicit anti-tumor immunity against HR+ breast cancer. 2) Determine the anti-tumor utility of an optimal Ad-PR vaccine with anti-PD-L1 ICIs as a means to elicit anti-tumor immunity against HR+ breast cancer. These studies we will determine if blocking PR can activate localized anti-tumor immunity, thereby sensitizing HR+ breast cancers to treatment with ICIs. In our first aim, we will determine if anti-progestin blockade of PR signaling can reverse localized immunosuppression of PR+ mammary tumors and if this approach synergizes with ICI combinations. In our second aim, we will utilize a novel PR-targeting vaccine to stimulate T cell immunity against PR as a novel means to drive T cell infiltration into HR+ tumors and invigorate local anti-tumor immunity. The PR vaccine will be tested alone, and in combination with ICIs, as an additional approach to sensitive these tumors to treatment with ICIs. If successful, these studies could enable our understanding of PR immune modulation in BC and allow for new approaches to immunologically treat HR+ BC, which has been refractory to current immunotherapeutic interventions.
