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Molecular Diagnostics

IL-33/ST2 signaling promotes constitutive and inductive PD-L1 expression and immune escape in oral squamous cell carcinoma



Loss-of-function of PD-L1 induces therapy resistance of anti-PD-1/L1 therapy, and the complex regulatory mechanisms are not completely understood. We previously reported that stroma-derived interleukin-33 (IL-33) promoted the progression of oral squamous cell carcinoma (OSCC). We here focused on the immune-regulation role of IL-33 and its receptor ST2 signaling in PD-L1-positive OSCC patients.


Activated T cells in in situ and peripheral blood were analyzed by IL-33/ST3 expression. Knockdown or overexpression of ST2 combined with IL-33/IFN-γ stimulation were performed to determine PD-L1 expression and PD-L1-dependent immune escape in OSCC/human T cells co-culture system, and OSCC orthotopic model based on humanized mouse with immune reconstitution and C57BL/6 mice models.


High IL-33/ST2 correlated with less activated T cells infiltration in situ and peripheral blood. Knockdown of ST2 down-regulated constitutive PD-L1 expression, whereas ST2 also promoted IL-33-induced PD-L1 Mechanistically, IL-33/ST2 activated JAK2/STAT3 pathway to directly promoted PD-L1 expression, and also activated MyD88/NF-κB signaling to up-regulate IFN-γ receptor (IFN-γR), which indirectly strengthen IFN-γ-induced PD-L1. Furthermore, ST2 is required for PD-L1-mediated immune tolerance in vitro and in vivo. ST2high OSCC patients have more PD-L1 and IFN-γR level in situ.


IL-33/ST2 signaling enhanced PD-L1-mediated immune escape, ST2high OSCC patients might benefit from anti-PD-1/L1 therapy.

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Fig. 1: Correlations between IL-33/ST2 and T cells activation in situ and blood.
Fig. 2: IL-33/ST2 signal in OSCC regulates the expression of PD-L1.
Fig. 3: The role of JAK2/STAT3 pathway in the regulation of PD-L1 expression by IL-33/ST2.
Fig. 4: The impacts of IL-33/ST2 signaling on IFN-γR/PD-L1 expression of tumor cells.
Fig. 5: ST2 knockdown promote the human CTL killing function in vitro and in vivo of Hu-PBMC mouse model.
Fig. 6: ST2 knockdown combines with anti-PD-L1 therapy show superior anti-tumor effects in OSCC.

Data availability

All of the data generated or analyzed in this study are included in this published article.


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Research was supported by grants by the National Natural Science Foundation of China (Grant No. 81902754, 82002865); Natural Science Foundation of Jiangsu Province (No. BK20190304, BE2020628); Nanjing Medical Science and Technology Development Foundation, Nanjing Department of Health (No. YKK21182, YKK20151).

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Authors and Affiliations



Conceptualization: LD, YHN and ZYW; data curation: MXZ; formal analysis: MXZ and YXS; methodology: LD, NSZ and YJH, and MXZ; investigation: NSZ, and MXZ; supervision: LD, YHN, and QGH; validation: YHN; Writing—original draft: LD and MXZ.

Corresponding authors

Correspondence to Zhiyong Wang, Yanhong Ni or Liang Ding.

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The authors declare no competing interests.

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Ethical approval for this study including tumor biopsy and serum collection was obtained from the Research Ethics Committee of Nanjing Stomatology Hospital (No.2019NL-009(KS)) and informed consent was obtained from the patients. The study was performed in accordance with the Declaration of Helsinki. All animal experiments were performed in accordance with Jiangsu Association for Laboratory Animal Science (Authorization Number: 220195073) and were subject to review by the animal welfare and ethical review board of Nanjing university.

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Zhao, M., He, Y., Zhu, N. et al. IL-33/ST2 signaling promotes constitutive and inductive PD-L1 expression and immune escape in oral squamous cell carcinoma. Br J Cancer (2022).

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