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STAT3 Induces Immunosuppression by Upregulating PD-1/PD-L1 in HNSCC
11 The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine, Ministry of Education, Wuhan, China.
Abstract:
Head and neck cancer is one of the most prevalent cancers around the world. Head and neck squamous cell carcinoma (HNSCC) accounts for nearly 90% of head and neck cancer. In recent years, significant advances have been made in immunotherapy for HNSCC. Although some clinical trials targeting immune checkpoints have shown success, the molecular mechanism for regulation of programmed death 1 (PD-1) and its ligand (PD-L1) is partially understood. In an effort to explore the effect of activation of signal transducers and activators of transcriptions (STAT3) on PD-1/PD-L1, the expression and correlation between phosphorylation of STAT3 and PD-1/PD-L1 were determined with immunostaining of human and mouse HNSCC tissue sections. PD-1/PD-L1 overexpression was found to be significantly associated with p-STAT3 in human and mouse HNSCC. Targeting STAT3 by a small molecule effectively inhibited the expression of PD-L1 in the CAL27 cell line. Furthermore, we found that blockade of STAT3 signaling downregulated PD-1/PD-L1 in a Tgfbr1/Pten 2cKO HNSCC mouse model. These findings suggest that STAT3 signaling plays an important role in PD-1/PD-L1 regulation and the antitumor immune response of HNSCC.
Insights
Signal transducer and activator of transcription 3 (STAT3) signaling promotes programmed death-1 (PD-1) and its ligand (PD-L1) expression in head and neck squamous cell carcinoma (HNSCC). Targeting STAT3 may enhance immunotherapy for HNSCC.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer with ongoing advances in immunotherapy.
- Immune checkpoint inhibitors targeting programmed death 1 (PD-1) and its ligand (PD-L1) show promise, but their regulatory mechanisms in HNSCC require further elucidation.
- Understanding the molecular pathways that control PD-1/PD-L1 expression is crucial for optimizing HNSCC immunotherapy.
Purpose of the Study:
- To investigate the role of signal transducer and activator of transcription 3 (STAT3) activation in regulating PD-1 and PD-L1 expression in HNSCC.
- To explore the correlation between phosphorylated STAT3 (p-STAT3) and PD-1/PD-L1 levels in HNSCC.
- To assess the therapeutic potential of targeting STAT3 signaling for HNSCC treatment.
Main Methods:
- Immunostaining was employed to analyze the expression and correlation of p-STAT3 with PD-1/PD-L1 in human and mouse HNSCC tissue sections.
- A small molecule inhibitor was used to target STAT3 in the CAL27 HNSCC cell line.
- STAT3 signaling blockade was evaluated in a Tgfbr1/Pten 2cKO HNSCC mouse model.
Main Results:
- Overexpression of PD-1 and PD-L1 was significantly associated with p-STAT3 in both human and mouse HNSCC.
- Inhibition of STAT3 using a small molecule effectively reduced PD-L1 expression in the CAL27 cell line.
- Blocking STAT3 signaling led to the downregulation of PD-1/PD-L1 in a preclinical HNSCC mouse model.
Conclusions:
- STAT3 signaling plays a significant role in the regulation of PD-1/PD-L1 expression in HNSCC.
- Targeting STAT3 represents a potential strategy to enhance antitumor immune responses in HNSCC.
- These findings provide insights into the molecular mechanisms underlying immunotherapy resistance and suggest novel therapeutic avenues for HNSCC.
