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

Dana E Rollison,Rossybelle P Amorrortu,Rebecca S Hesterberg,Jane L Messina,Afua A Akuffo,Pearlie K Epling-Burnette,Michael J Schell,Neil A Fenske,Dennis O Adeegbe,Basil S Cherpelis,Yayi Zhao

doi:10.3389/fmed.2021.735585

Dana E Rollison, Rossybelle P Amorrortu + Show 9 more

Open Access

https://doi.org/10.3389/fmed.2021.735585

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Abstract

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.

Highlights

Keratinocyte carcinomas (KC) including cutaneous squamous cell carcinoma and basal cell carcinoma (BCC) are the most commonly diagnosed cancers in the U.S [1,2,3], with more than five million KC cases diagnosed each year [4]
While chronic lifetime Ultraviolet radiation exposure (UVR) results in the accumulation of UVRinduced DNA damage [9], leading to skin carcinogenesis [10, 11], UVR may contribute to cutaneous squamous cell carcinoma (cuSCC) development through an immunosuppressive pathway
ANone of the cuSCC tumors were graded as a solar elastosis level of 0, the category was not included in the table

Summary

Introduction

Keratinocyte carcinomas (KC) including cutaneous squamous cell carcinoma (cuSCC) and basal cell carcinoma (BCC) are the most commonly diagnosed cancers in the U.S [1,2,3], with more than five million KC cases diagnosed each year [4]. CuSCC typically comprised 20% of KC [1, 5] trends are increasing with a recent study reporting a 1:1 ratio of cuSCC to BCC in adults ages 65+ [4]. Ultraviolet (UV) radiation exposure (UVR) is the major environmental risk factor for KC, and chronic lifetime UVR has been associated with cuSCC risk [2, 7,8,9]. While chronic lifetime UVR results in the accumulation of UVRinduced DNA damage [9], leading to skin carcinogenesis [10, 11], UVR may contribute to cuSCC development through an immunosuppressive pathway. Immunosuppression is a wellestablished risk factor for cuSCC, with heart, kidney, blood, and marrow transplant patients experiencing 16- to 68- fold risks of cuSCC compared to the general population [12, 13]. While mouse studies have shown that UVR is immunosuppressive [15, 16], no epidemiologic studies have sought to measure the interplay between UVR and immune function in relation to cancer etiology in humans

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