title: Quantification of tumor infiltrating Foxp3+ regulatory T cells enables the identification of high-risk patients for developing synchronous cancers over upper aerodigestive tract.
abstract: OBJECTIVE
  Patients 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.
  
  
  METHODS
  Tumor 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).
  
  
  RESULTS
  The 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/mm(2) 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.
  
  
  CONCLUSIONS
  A 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.
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan; Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan. Electronic address: warrengodr@gmail.com.
authors.forename: Wen-Lun
authors.initials: WL
authors.lastname: Wang
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan. Electronic address: weilun1@mail.ncku.edu.tw.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Chang
authors.affiliation: Department of Pathology, National Cheng Kung University Medical Center, Tainan, Taiwan; Department of Pathology, Ton-Yen General Hospital, Hsin-Chu, Taiwan. Electronic address: yanghsiaobai@yahoo.com.tw.
authors.forename: Hsiao-Bai
authors.initials: HB
authors.lastname: Yang
authors.affiliation: Department of Pathology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan. Electronic address: B8701079@gmail.com.
authors.forename: I-Wei
authors.initials: IW
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan. Electronic address: fattoo@gmail.com.
authors.forename: Ching-Tai
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan. Electronic address: chiyang1112@gmail.com.
authors.forename: Chi-Yang
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan. Electronic address: jawtown@gmail.com.
authors.forename: Jaw-Town
authors.initials: JT
authors.lastname: Lin
authors.affiliation: Institute of Clinical Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Medical Center, Tainan, Taiwan. Electronic address: sheubs@mail.ncku.edu.tw.
authors.forename: Bor-Shyang
authors.initials: BS
authors.lastname: Sheu
mesh_terms: D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D054422:Chemokine CCL22 / Q000378:metabolism; D003430:Cross-Sectional Studies; D004938:Esophageal Neoplasms / Q000473:pathology; D051858:Forkhead Transcription Factors; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008875:Middle Aged; D012307:Risk Factors; D050378:T-Lymphocytes, Regulatory / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D054422:Chemokine CCL22; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007378:Interleukins; D053773:Transforming Growth Factor beta1
keywords: Esophageal cancer; Head and neck cancer; Immunity; Regulatory T cell; Surveillance; Synchronous neoplasm