Highly Immunosuppressive Hladr(Hi) Regulatory T Cells Are Associated With Unfavorable Outcomes In Cervical Squamous Cell Carcinoma

Regulatory T cells (Tregs) are crucial for the maintenance of peripheral tolerance, but they also limit beneficial responses through cancer-induced immunoediting. The roles of Treg subsets in cervical squamous cell carcinoma (CSCC) are currently unknown. Here, we aimed to perform an extensive study with an increased resolution of the Treg compartment in the peripheral blood and tumor tissues of CSCC patients. We first identified that an HLADR(hi) Treg population in the peripheral blood was significantly increased in CSCC patients compared to precancer patients and healthy donors. We found that HLADR(hi) Tregs express high levels of a panel of inhibition and activation markers and the TCR-responsive transcription factors BATF and IRF4. However, this Treg subset showed reduced calcium influx after TCR crosslinking. In addition, HLADR(hi) Tregs are highly proliferative and vulnerable to apoptosis. Further studies demonstrated that the HLADR(hi) Tregs display high levels of suppressive activity. Quantitative multiplexed immunohistochemistry revealed that an increase in the number of tumor-infiltrating HLADR(hi) Tregs is associated with unfavorable classical risk parameters of advanced disease stage and stromal invasion. Context-based quantification revealed that a high frequency of stromal HLADR(hi) Tregs in patients is significantly associated with worse progression-free survival. In the current study, we characterized a population of highly activated and immunosuppressive HLADR(hi) Tregs in CSCC patients. An increased HLADR(hi) Treg frequency may be a potential biomarker to stratify CSCC patients and evaluate therapeutic efficacies in personalized immuno-oncology studies.