Kansas IDeA Network of Biomedical Research Excellence (K-INBRE) - suppl WH

University Of Kansas Medical Center, Kansas City KS

Investigators

Linked publications, trials & patents

Abstract

ABSTRACT Title of the supplement proposal: “Progesterone promotes breast cancer immune evasion through downregulation of antigen presentation” Approximately 75% of all breast cancers (BC) are classified as hormone receptor positive (HR+), the majority expressing both the 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 will develop resistance and die from metastatic disease. Thus, new therapeutic targets and strategies are desperately needed for the treatment of endocrine-resistant disease. While existing therapies target ER pathways, there are currently no clinical means to target PR, despite multiple studies implicating PR in progression outcomes in HR+ BC. This may be due to a lack of knowledge in how PR contributes to BC progression. Our recent studies have unexpectedly revealed a significant immune modulatory role for PR. Our hypothesis is that progesterone, working through the progesterone receptor (PR), downregulates antigen processing and presentation (APP), thus allowing for PR-positive breast tumor escape from immune recognition and clearance by CD8+ T cells. We will test this hypothesis with the following Specific Aims: 1) Does PR signaling downregulate the expression of genes involved in antigen processing and presentation? 2) Does PR activation promote decreased antigen presentation and tumor cell killing by CD8+ T cells? 3) Does PR activation lead to decreased antigen presentation and increased mammary gland tumor growth in vivo? First, we will determine the timeline through which PR/progesterone downregulates APP gene expression and use ChIP assays to determine if PR- dependent downregulation of APP genes is mediated through direct binding of PR to regulatory regions of APP genes. Second, using T cells from T cell receptor (TCR) transgenic mice, we will determine if PR-mediated downregulation of APP genes translates to decreased antigen presentation in MHC Class I molecules and subsequent protection from T cell-mediated tumor cell killing. Third, to determine if these phenotypes translate to protection from mammary tumor cell killing in vivo, we will determine how treatment with progesterone and anti-progestins (blocking PR activation) impacts syngeneic mammary tumor growth and recognition by CD8+ T cells in vivo. Completion of these Specific Aims will determine how PR downregulates antigen presentation and recognition by CD8+ T cells, and if this effect can be reversed using anti-progestins. These experiments will provide new insight into the function of PR, an essential but understudied protein in breast cancer. Blocking PR’s activity could lead to new therapeutic strategies for ER/PR-positive tumors that progress on treatment with current ER/estrogen-based therapies.