Abstract B028: Vigorous physical activity associated changes in immune cell infiltrate are linked with reduced prostate tumour aggressiveness
Authors: Huang Lanshan , Halliday Sophia , Olsson Linnea , Hamilton Alina , Kirk Erin , Farnan Laura , Gerstel Adrian , Craig Stephanie , Finn Stephen , Wilson Melissa , Troester Melissa , Butler Eboneé , Bensen Jeannette , Wobker Sara , Allott Emma 
Published: June 2023

Abstract
Vigorous physical activity has been associated with lower risk of fatal prostate cancer and improved cancer-specific outcomes. However, the mechanisms contributing to this relationship are not understood. The current study characterized inflammation in prostate cancer tissue and evaluated features of the immune microenvironment related to physical activity and prostate cancer aggressiveness. We studied 119 men with prostate cancer participating in the University of North Carolina Health Registry/Cancer Survivorship Cohort who underwent radical prostatectomy. Structured questionnaires were administered at patients' study entry to assess physical activity. Digital image analysis of H&E-stained tissue sections using QuPath was applied to quantify Tumour Infiltrating Lymphocytes (TILs) in glands and stroma of tumor and adjacent normal regions. Nanostring gene expression profiling was performed on tumour tissue and a 50-gene signature utilized to predict immune cell types. ERG gene expression was used as a surrogate of TMPRSS2:ERG fusion status. Logistic regression was used to test associations of inflammation features with tumour aggressiveness and recreational physical activity measures. Cox proportional hazards analysis was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between immune cell types and risk of prostate cancer progression, with validation in a separate study of 101 radiation-treated prostate cancer patients. Our study comprised 77% white and 23% black men, and 25% of men had Gleason grade ≥4+3, 29% men reported recreational vigorous activity prior to diagnosis of prostate cancer. Acute tumour inflammation affected 30% of men, while 53% showed acute inflammation of adjacent tissue. TILs were more abundant in glands than stroma; two-fold more in tumour and five-fold more in adjacent tissue. Frequency of inflammation was similar between ERG-positive and ERG-negative tumours. An inverse relationship was observed between recreational vigorous activity and TILs abundance. Expression of the immune gene signature was also significantly lower in men reporting any recreational vigorous activity compared to those reporting none (P=0.044), driven by reduced gene expression-predicted abundance of Th cells, exhausted CD8 T cells, macrophages and neutrophils. Moreover, T cells, Tfh, Treg, exhausted CD8 T cells and macrophages were significantly increased in men with Gleason grade ≥4+3 or clinical stage ≥III. Treg abundance was positively associated with prostate cancer progression (HR, 1.35; 95%CI 1.03-1.78) after adjusting for age and race, which was further strengthened in ERG-positive patients (HR, 1.60; 95%CI 1.03-2.47). We show that the immune landscape in prostate cancer is altered in men reporting vigorous physical activity. Immune cell types associated with an immunosuppressive microenvironment, including exhausted CD8 T cells, Tregs, and macrophages, may be potential candidate mechanisms linking recreational vigorous activity with reduced prostate tumour aggressiveness and improved outcomes.
Citation Format: Lanshan Huang, Sophia Halliday, Linnea Olsson, Alina Hamilton, Erin Kirk, Laura Farnan, Adrian Gerstel, Stephanie Craig, Stephen Finn, Melissa Wilson, Melissa Troester, Eboneé Butler, Jeannette Bensen, Sara Wobker, Emma Allott. Vigorous physical activity associated changes in immune cell infiltrate are linked with reduced prostate tumour aggressiveness [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B028.