Abstract 5069: Inflammatory cytokine localization in the prostate tumor microenvironment and their association with prostate cancer racial disparities

Abstract

Abstract Prostate cancer (PCa) is the 3rd leading cause of cancer-related deaths in American men. The major risk factors for PCa development include advanced age, family history and African ancestry. Chronic inflammation has been implicated as a major contributor to PCa and genes involved in inflammatory pathways are reported as more prevalent in tumors from African American (AA) versus Caucasian American (CA) men. Specifically, interleukin-1β (IL1β), IL6, IL8, and IL10 have been identified as over-expressed in the tumor microenvironment of AA men. These interleukins are in involved in the attraction, activation or maintenance of innate immune cells such as neutrophils and macrophages. However, it is not well understood where these interleukins are expressed in the prostate and what cell types produce them. We aim to address these specific questions in this study. The expression pattern and cellular localization of IL1β, IL6, IL8 and IL10 were evaluated using a highly specific RNA in situ hybridization (RISH) assay to analyze formalin-fixed paraffin-embedded tissues of low grade (Gleason ≤ 3+4) and higher grade (Gleason ≥ 4+3) PCa from AA and CA men. IL8 expression was additionally assessed by RISH in two unique tissue microarray (TMA) sets; i) primary prostate tumors obtained by radical prostatectomy from AA and CA men, matched for patient age, tumor grade and stage; ii) distant metastatic tissues obtained by autopsy. Immunohistochemical analysis of neutrophils (CD66ce) and RISH for macrophages (CD68) was used to assess the expression pattern of these immune cells within the same cohorts. Limited IL1β and IL10 expression was observed across all cases. IL6 expression was largely confined to the stromal compartment in endothelial cells and areas of acute inflammation. Modest IL6 expression was observed in atrophic epithelial cells. IL6 was never seen in tumor cells. IL8 was the most abundantly detected cytokine within our cohort and was significantly increased in higher grade cases. In benign regions, IL8 expression was predominantly observed in epithelial cells in regions of prostatic atrophy and in areas surrounding corpora amylacea. We observed marked IL8 expression in urothelial cells in most cases. IL8 expression was also apparent in multiple tumors, both in tumor cells and infiltrating immune cells. Tumor-infiltrating macrophages were markedly increased within a subset of tumors, but did not appear to express IL8. Conversely, a subset of neutrophils expressed IL8. Neutrophils were significantly increased in benign tissues from men with higher grade PCa, particularly in AA men. IL8 expression was also observed in a subset of distant metastases, particularly in liver metastases. There is differential expression of cytokines among men with PCa, and IL8 is the most abundant among the ones we analyzed. Our future studies aim to determine a role for IL8 in prostate carcinogenesis. Citation Format: Janielle P. Maynard, Onur Ertunc, Angelo M. De Marzo, Karen S. Sfanos. Inflammatory cytokine localization in the prostate tumor microenvironment and their association with prostate cancer racial disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5069.