Quantification of tumor infiltrating Foxp3+ regulatory T cells enables the identification of high-risk patients for developing synchronous cancers over upper aerodigestive tract

• Synchronous cancers over upper aerodigestive tract lead to poor prognosis.
• The tumor infiltrating Foxp3+ regulatory T cells were higher in synchronous SCC.
• The Foxp3+ regulatory T cell density in tumor was correlated with serum IL-10 level.
• The serum IL-10 level was higher in synchronous SCC than in non-synchronous ones.
• Foxp3+ Treg number stratifies the synchronous cancer risk for surveillance program.

SummaryObjectivesPatients with squamous cell carcinomas (SCC) of upper aerodigestive tract, either over head and neck (HNSCC) or esophagus (ESCC), frequently developed synchronous multiple cancers, leading to worse prognosis. This study validated whether suppression of host cancer immunosurveillance mediated by regulatory T cells (Treg) may predispose to the development of synchronous cancers.MethodsTumor tissues of 200 patients (100 ESCC only, 50 HNSCC only, and 50 synchronous SCCs) were quantitatively accessed for the tumor infiltrating Treg by immunohistochemistry. The density of Treg was also correlated to the level of Treg-associated inhibitory cytokines (IL-10, IL-35 and TGF-β1), and chemokine (CCL22).ResultsThe density of tumor infiltrating Treg in the index tumor (i.e. the first malignancy diagnosed) of synchronous SCC group was higher than those of HNSCC or ESCC only (p < 0.05). Selecting the optimal cut-off value of Treg density as 34.6 cells/mm2 by ROC curve, an increased Treg density of the index tumor can be an independent factor for developing synchronous SCCs (OR: 6.13; 95% CI: 2.84–13.26). The Treg density was positively correlated with serum IL-10 level and the degree of CCL22-positive cells infiltration in tumor. Furthermore, the serum inhibitory cytokine IL-10 level was higher in synchronous SCC than in non-synchronous ones (p < 0.001), that indicated the cellular immunosuppression in patients with synchronous cancers.ConclusionsA more severe defect in cellular immunity may predispose to multifocal tumor. The Treg cell number in SCC may serve as a novel predictive biomarker for the risk of synchronous cancer development to initiate a proper surveillance program.