Stromal interleukin-33 promotes regulatory T cell-mediated immunosuppression in head and neck squamous cell carcinoma and correlates with poor prognosis
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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.
KeywordsInterleukin-33 Regulatory T cells Head and neck squamous cell carcinoma Prognosis Tumor microenvironment
Laryngeal squamous cell carcinoma
YW, WS, and WW conceived and designed the experiments. HL and YW performed the experiments. HL and YZ evaluated immunohistochemistry. XW, LC, and WS made important contributions to collecting blood and tissue samples. HL, YW, and WW wrote the manuscript. VWYL commented on and edited the manuscript. All authors read and approved the final manuscript.
Yi-hui Wen was supported by grants from the Natural Science Foundation of Guangdong Province, China (Nos. 2018A030313667, 2017A030310362, and 2015A030310236). Wei-ping Wen was supported by Guangzhou Science and Technology Programme (No. 201605030003) and the Sun Yat-Sen University 5010 Plan (2010004). Vivian Wai Yan Lui was supported by the General Research Fund from the Research Grant Council, Hong Kong (No. 1711484 and No. 17121616), Theme-based Research from the Research Grant Council, Hong Kong (T12-401/13-R), and a Direct Grant for Research (No. 2016.095), the Chinese University of Hong Kong. Wei Sun was supported by the Natural Science Foundation of China (No. 81602365) and Natural Science Foundation of Guangdong Province, China (No. 2016A030310153).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (Approval no. 2012-349). Informed consent was obtained from all participants prior to enrollment in the study.
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