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IL-33/ST2 signaling promotes constitutive and inductive PD-L1 expression and immune escape in oral squamous cell
Mengxiang Zhao1,2,3, Yijia He1, Nisha Zhu1
1Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
IL-33/ST2 signaling enhanced PD-L1-mediated immune escape, ST2high OSCC patients might benefit from anti-PD-1/L1 therapy.
Insights
Interleukin-33 (IL-33) and its receptor ST2 signaling promote PD-L1 expression and immune escape in oral squamous cell carcinoma (OSCC). High ST2 levels in OSCC patients may predict benefit from anti-PD-1/L1 therapy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Loss-of-function of PD-L1 can lead to resistance against anti-PD-1/L1 therapies, with incompletely understood regulatory mechanisms.
- Stroma-derived interleukin-33 (IL-33) has been previously implicated in promoting oral squamous cell carcinoma (OSCC) progression.
- This study investigates the immune-regulatory role of IL-33 and its receptor ST2 signaling in PD-L1-positive OSCC.
Purpose of the Study:
- To elucidate the role of IL-33/ST2 signaling in regulating PD-L1 expression and immune escape in OSCC.
- To determine the correlation between IL-33/ST2 expression and T cell activation in OSCC patients.
- To investigate the potential of ST2 as a predictive biomarker for anti-PD-1/L1 therapy response in OSCC.
Main Methods:
- Analysis of activated T cells in situ and peripheral blood based on IL-33/ST2 expression.
- In vitro and in vivo experiments using OSCC cell lines and mouse models (humanized and C57BL/6) with ST2 knockdown/overexpression and IL-33/IFN-γ stimulation.
- Assessment of PD-L1 expression, PD-L1-dependent immune escape, and signaling pathways (JAK2/STAT3, MyD88/NF-κB).
Main Results:
- High IL-33/ST2 expression correlated with reduced activated T cell infiltration in OSCC patients.
- ST2 knockdown decreased constitutive PD-L1 expression, while ST2 promoted IL-33-induced PD-L1 expression.
- IL-33/ST2 signaling activates JAK2/STAT3 for direct PD-L1 upregulation and MyD88/NF-κB for IFN-γ receptor upregulation, indirectly enhancing IFN-γ-induced PD-L1.
- ST2 is essential for PD-L1-mediated immune tolerance in vitro and in vivo.
- ST2high OSCC patients exhibited higher in situ PD-L1 and IFN-γR levels.
Conclusions:
- IL-33/ST2 signaling enhances PD-L1-mediated immune escape in OSCC.
- OSCC patients with high ST2 expression may potentially benefit from anti-PD-1/L1 therapies.
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