Frequency, suppressive capacity, recruitment and induction mechanisms of regulatory T cells in sinonasal squamous cell carcinoma and nasal inverted papilloma

PLoS One. 2015 May 28;10(5):e0126463. doi: 10.1371/journal.pone.0126463. eCollection 2015.

Abstract

Background: Sinonasal squamous cell carcinoma (SSCC) and nasal inverted papilloma (NIP) represent the predominant type of malignant and benign tumors in sinonasal tract, respectively. CD4+ CD25+ Foxp3+ natural regulatory T (Treg) cells might play critical role(s) in the suppression of anti-tumor immune response and thus shed light on tumor progression from benign to malignant.

Objective: This study aimed to evaluate the frequency and suppressive capacity of Treg cells in SSCC compared to NIP and further to explore the underlying mechanisms.

Patients and methods: Frequencies of Treg, Th1 and Th2 cells were evaluated by flow cytometry in tissue homogenate and peripheral blood from 31 SSCC patients, 32 NIP patients and 35 normal controls. Treg cells were tested for regulatory function by co-culture with effector T cells. CCR4 and its ligands, CCL22 and CCL17, were analyzed by flow cytometry and Luminex, respectively. The chemoattractant properties of CCR4/CCL22 and CCR4/CCL17 for Treg cells were assessed using the Boyden chamber technique, to elucidate the potential mechanisms of Treg recruitment in tumor microenvironment. Treg cells induction via TGF-β was assessed with transwells after local CD4+ Foxp3+ T cells were assessed by immunohistochemistry and TGF-β concentration was measured by Luminex.

Results: Tumor-infiltrating Treg cells increased significantly from normal to NIP to SSCC (P ≤ 0.001 for normal vs. NIP and P = 0.004 for NIP vs. SSCC). Significantly elevated frequency and enhanced suppression capacity of circulating Treg cells in SSCC were detected compared to NIP and healthy controls, concomitant with Th1 decrease and Th2 increase. Apparently increased CCL22 attracted CCR4-expressing Treg cells to tumor microenvironment in SSCC, compared to NIP. SSCC produced significantly more TGF-β than NIP and thus possessed greater potential for Treg cell induction.

Conclusion: Frequency and suppressive capacity of Treg cells enhanced with progression of malignancy from NIP to SSCC. Circulating Treg cells were recruited to tumor tissue via CCR4/CCL22 signalling, whereas tumor-synthesised TGF-β contributed to induction of peripheral Treg cells.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / pathology
  • Chemokine CCL17 / immunology
  • Chemokine CCL22 / immunology
  • Female
  • Humans
  • Male
  • Maxillary Sinus Neoplasms / immunology*
  • Maxillary Sinus Neoplasms / pathology
  • Middle Aged
  • Nasal Polyps / immunology*
  • Nasal Polyps / pathology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Transforming Growth Factor beta / immunology
  • Tumor Microenvironment / immunology*

Substances

  • CCL17 protein, human
  • CCL22 protein, human
  • Chemokine CCL17
  • Chemokine CCL22
  • Transforming Growth Factor beta

Grants and funding

This work was supported by grants from the Program for Changjiang Scholars and Innovative Research Team (IRT13082), the National Science Fund for the Major International Joint Research Program (81420108009), Beijing Natural Science Foundation (7131006), Ministry of Health Foundation (201202005), the Capital Health Research and Development of Special (2011-1017-06), the Special Fund of Sanitation Elite Reconstruction of Beijing (2009-2-007) and Beijing Health Bureau Program for high level talents (2009-2-007 and 2011-3-043).