Stromal interleukin-33 promotes regulatory T cell-mediated immunosuppression in head and neck squamous cell carcinoma and correlates with poor prognosis

Yi hui Wen, Han qing Lin, Hang Li, Yi Zhao, Vivian Wai Yan Lui, Lin Chen, Xing mei Wu, Wei Sun, Wei ping Wen

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Regulatory T cells (Tregs) mediate immunosuppressive signals that can contribute to the progression of head and neck squamous cell carcinoma (HNSCC). Interleukin-33 (IL-33) is defined as an ‘alarmin’, an endogenous factor that is expressed during tissue and cell damage, which has been shown to promote Treg proliferation in non-lymphoid organs. However, the interaction between IL-33 and Tregs in the HNSCC tumor microenvironment remains uncertain. In this study, we examined IL-33 + and Foxp3 + cells by immunohistochemistry in 68 laryngeal squamous cell cancer patients, followed by functional analysis of IL-33 in Tregs. In addition, the suppressive function of Tregs was assessed by cell proliferation assays. The level of stromal IL-33 was significantly upregulated in advanced versus early stage HNSCC patients and positively correlated with Foxp3 + Treg infiltration as well as a poor prognosis. ST2 is regarded as the only receptor of IL-33. Infiltrated ST2-expressing Tregs were responsive to IL-33, and the percentage of Tregs was increased upon IL-33 stimulation. Functional investigation demonstrated that IL-33 increased the proportion of Foxp3 + GATA3 + Tregs and improved the suppressive functions of Tregs by inducing IL-10 and TGF-β1 as well as decreasing the proliferation of responder T cells. Blockade of ST2 abrogated the immunosuppression caused by IL-33. Our data demonstrate that stromal IL-33 both expands the Treg population and enhances their functions in the tumor microenvironment. Furthermore, stromal IL-33 has prognostic value for tumor progression. Thus, stromal IL-33 is a potential target for future HNSCC immunotherapy.

Original languageEnglish (US)
Pages (from-to)221-232
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume68
Issue number2
DOIs
StatePublished - Feb 13 2019
Externally publishedYes

Keywords

  • Head and neck squamous cell carcinoma
  • Interleukin-33
  • Prognosis
  • Regulatory T cells
  • Tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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