Abstract 3492: Circulating immunosuppressive regulatory T cells and risk of incident cutaneous squamous cell carcinoma

Background: Ultraviolet radiation exposure (UVR) and immunosuppression are established risk factors for cutaneous squamous cell carcinoma (cuSCC). UVR can lead to systemic immune suppression as well as antigen specific immune tolerance due to generation of regulatory T cells (“Tregs”) which are known to have immunosuppressive effects. However, UVR-related immune responses in association with cuSCC risk have not been well studied in immunocompetent individuals. Objective: To determine whether circulating Tregs are associated with increased risk of cuSCC among individuals with higher UVR, we examined baseline Tregs, UVR, and subsequent cuSCC incidence among a subset of participants enrolled in a prospective cohort study of individuals undergoing skin cancer screening. Methods: 350 patients ages 60+ years with no prevalent skin cancer at the time of enrollment were recruited from the University of South Florida Dermatology Clinic in July 2014- July 2015 and followed for incident cuSCC up to four years later. At the baseline visit, blood was obtained, and a spectrophotometer was used to measure skin pigmentation at a sun-unexposed site (the axilla) and two sun-exposed sites (the forehead and the upper forearm). Recent UVR was quantified as the difference in readings between the sun-exposed and sun-unexposed sites. Using flow cytometry assays, lymphocyte samples were examined for Tregs (CD4+ CD25+ CD127low FoxP3+), and proportions of Tregs with enhanced immunosuppressive function (CD45RA−/CD27− Tregs) and skin tissue affinity (CLA+ Tregs, CCR4high Tregs) were determined. Associations between baseline Tregs and incident cuSCC were described using Cox Proportional Hazards, adjusting for age and sex, with and without stratification by higher versus lower levels of recent UVR. Results: Higher cuSCC incidence was observed in patients with higher circulating levels of CD45RA−/CD27− Tregs at baseline, as well as CLA+ Tregs, although the associations were not significant. Those with higher circulating CCR4hi Tregs at baseline had a 90% increased risk of developing a subsequent, incident cuSCC compared to those with lower levels (Hazard Ratio (HR)=1.90, 95% Confidence Interval (CI)= 1.03-3.49). Furthermore, participants with higher CCR4hi Tregs and higher UVR were four times more likely to develop an incident cuSCC compared to participants with lower CCR4hi Tregs and lower UVR (HR=4.11, 95% CI= 1.22-13.90). Conclusions: CCR4hi Tregs were associated with increased cuSCC risk, particularly among individuals with higher recent UVR exposure. CCR4hi Tregs may migrate out of circulation and into the skin in response to UVR-associated skin damage and possible release of local antigens, possibly influencing carcinogenesis by suppressing the immune response to UVR-damaged cells. Further research is needed to investigate the underpinning biology so that new opportunities for screening and prevention may be identified. Citation Format: Dana E. Rollison, Neil A. Fenske, Basil Cherpelis, Jane L. Messina, Yayi Zhao, Rossybelle P. Amorrortu, Rebecca Hesterberg, Pearlie K. Epling-Burnette. Circulating immunosuppressive regulatory T cells and risk of incident cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3492.