Immune microenvironment in BPH pathogenesis

ABSTRACT – PROJECT 2 Benign prostatic hyperplasia affects the majority of men in later life and leads to considerable dysfunction. Current treatments do not address the pathophysiology of the disease but rather target the overall prostate physiology. The goal of our proposal is to identify BPH (Benign Prostatic Hyperplasia) specific treatments by uncovering its pathophysiology. BPH is marked by proliferation of both epithelial and stromal cells in the transition zone of the prostate. This expansion of tissue surrounding the prostatic urethra presumably gives rise to many of the lower urinary tract symptoms (LUTS) associated with BPH. A number of biologic pathways have been proposed to drive BPH including epithelial or stromal senescence, inflammation possibly related to infection, and aberrant activation of developmental pathways. We have recently performed gene expression profiling of BPH and identified at least two subtypes of BPH with possible therapeutic implications. One of the two most significantly differentially expressed genes in our study is CXCL13 which modulates the immune response. The CXCL13 finding represents an important lead in understanding how the immune response is established in BPH. We hypothesize that immune-related pathways play a significant role in BPH pathophysiology and that pathways associated with CXCL13 are drivers. The Aims of this proposal undertake to identify differences in immune response between BPH and normal prostate and to uncover important pathophysiology relationships that arise from these differences. In Aim 1, we will profile immune cell types in BPH and normal prostate using MIBI-TOF (Multiplexed Ion Beam Imaging by Time-Of-Flight) to measure 14 different immune cells and understand their spatial relationships with the epithelium and stroma. In Aim 2, we will identify spatial relationships and interactions between immune and other cell types. We will do this by combining RNA profiling of the stromal and epithelial compartments with multiplex IHC and computational modeling. In Aim 3, we will determine whether CXCL13 expression and accompanying immune cells is part of an immune response or a senescence response. We will examine whether senescent cell accumulation correlates with CXCL13 expression and BPH subtypes. We will also look for the presence of B and/or T cell clonality.