Abstract 61: Obesity-induced T cell senescence contributes to prostate cancer progression
Authors: Alejandra De Angulo, Peyton Travis, Christopher Jolly, Linda deGraffenried
Journal: Cancer Research (2018)

Abstract Obese men are at greater risk of developing an aggressive form of prostate cancer. The T cell population from obese subjects have shown signatures of cell senescence including shortened telomeres and elevated production of proinflammatory cytokines. The objective of our studies is to better understand the cellular and molecular basis for altered T cell anti-prostate tumor immunity in obesity, and whether this altered immune function contributes to the worse outcomes observed in obese patients. To investigate whether obesity induces a pro-inflammatory senescent phenotype in CD4+ T cells, splenic CD4+ T-cells from 10-week-old male C57Bl/6 mice were isolated and, either pre-stimulated or co-stimulated with anti CD3/CD28 and conditioned media (CM) from macrophages stimulated under obese or normo-weight conditions. After 24 hours conditioned media from these CD4+ T cells was collected, and their relative cytokine expression profile was analyzed. The CD28 receptor is expressed on CD4+ T cells and provides co-stimulatory signals required for T cell activation. CD28 activation results in phosphorylation of Akt. Lack of Akt phosphorylation in CD4+ T cells after CD3+/CD28+ stimulation indicates CD4+ T cell dysfunction and senescence. Fresh murine splenic CD4+ T cells were isolated and stimulated with anti CD3/CD28 under obese or control conditions. Akt1 phosphorylation levels were assessed using Western blot analysis. To determine if obese conditions modify the impact of CD4+ T cell dysfunction on prostate cancer cell signal transduction pathways, prostate cancer epithelial cells were exposed to obese or control CD4+ T-cells CM for 30 minutes and western blot analysis was used to evaluate the modulation of key pro- and anti-tumorigenic pathways. Matrigel Invasion chambers were used to determine if obesity-modified CD4+ T cell CM impacts the invasive capacity of prostate epithelial cells. Obese conditions suppressed the expression of IFN-γ and IL-2 in CD4+ T-cells. Data also suggests that T cells exposed to obese conditions suppress STAT1 activation in prostate cancer cells. Additionally, obese conditions up-regulated the expression of IL-6 and IL-10 in CD4+ T-cells when compared to control. Importantly our data also suggests that T cells exposed to obese conditions induce STAT3 activation in prostate cancer cells. Preliminary data also suggests that obesity-modified CD4+ T cell CM impacts the invasive capacity of prostate cancer cells. Obesity may induce CD4+ T cell dysfunction, limiting their tumor suppressing activity. Findings form this study could substantially advance fundamental understanding of the ways in which obesity alters T cells, thereby promoting uncontrolled tumor growth and mortality from prostate cancer. This study could also provide a framework for future translational research aimed at improving the effectiveness of therapies in obese patients. Citation Format: Alejandra De Angulo, Peyton Travis, Christopher Jolly, Linda deGraffenried. Obesity-induced T cell senescence contributes to prostate cancer progression [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 61.