Data_Sheet_1_Circulating Immunosuppressive Regulatory T Cells Predict Risk of Incident Cutaneous Squamous Cell Carcinoma.docx

Ultraviolet radiation exposure (UVR) is a risk factor for cutaneous squamous cell carcinoma (cuSCC) and has been shown to be positively associated with circulating immunosuppressive regulatory T cells (“Tregs”). However, the risk of cuSCC in association with circulating Tregs has not been studied. The aim of this study was to determine whether circulating Treg levels are associated with cuSCC development, particularly in the context of high UVR. Blood and spectrophotometer-based UVR measurements were obtained on 327 immunocompetent individuals undergoing routine skin cancer screenings at baseline and followed for up to 4 years for incident cuSCC development within a prospective cohort study. Proportions of phenotypically distinct Tregs, especially CCR4hi and CLA+ cells which are associated with activation and homing, respectively, were measured by flow cytometry. Tregs in cuSCC tumors were assessed using immunohistochemistry and graded for solar elastosis, a measure of cumulative UVR damage. Of several Treg phenotypes examined, higher levels of circulating CCR4hi Tregs at baseline were significantly associated with increased risk of subsequent cuSCC; those with higher levels of both CCR4hi and UVR were four times more likely to develop cuSCC compared to those with lower levels of both (Hazard Ratio = 4.11, 95% CI = 1.22–13.90). Within cuSCC tumors, CCR4hi Tregs were positively associated with solar elastosis. Results show that a higher proportion of CCR4hi peripheral Tregs predicts incident cuSCC up to 4 years, especially among highly UV-exposed individuals. Research of the underpinning biology of Tregs in UVR-associated skin damage may possibly reveal novel opportunities for screening, prevention, and treatment.

紫外辐射暴露（UVR）是皮肤鳞状细胞癌（cuSCC）的致病因素之一，且已被证实与循环中的免疫抑制性调节性T细胞（“Tregs”）呈正相关。然而，循环Tregs与cuSCC风险之间的关系尚未得到研究。本研究旨在确定循环Treg水平是否与cuSCC的发生发展相关，尤其是在高UVR的背景下。在基线时，对327名进行常规皮肤癌筛查的免疫健全个体进行了血液和分光光度计法测量的UVR数据收集，并在此前瞻性队列研究中对其进行了长达4年的随访，以观察cuSCC的发生。通过流式细胞术测量了具有不同表型的Tregs比例，特别是与激活和归巢相关的CCR4hi和CLA+细胞。使用免疫组化技术评估了cuSCC肿瘤中的Tregs，并对累积UVR损伤指标——太阳弹性纤维变性进行了分级。在所检查的几种Treg表型中，基线时循环CCR4hi Treg水平较高者与后续cuSCC风险增加显著相关；同时具有较高CCR4hi和UVR水平者，相较于两者水平较低者，发生cuSCC的可能性增加四倍（风险比=4.11，95%置信区间=1.22–13.90）。在cuSCC肿瘤中，CCR4hi Tregs与太阳弹性纤维变性呈正相关。结果表明，CCR4hi外周Treg比例较高可预测长达4年的cuSCC发生，尤其是在高紫外线暴露的人群中。对UVR相关皮肤损伤中Treg的潜在生物学机制的研究，可能揭示新的筛查、预防和治疗机会。