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In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients
Yutaro Kondo1, Susumu Suzuki2,3, Shoya Ono1
1Department of Maxillofacial Surgery, Aichi Gakuin University School of Dentistry, Nagoya 464-0821, Japan.
Abstract:
The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment.
Insights
Programmed death ligand-1 (PD-L1) expression in oral cancer is influenced by epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling pathways. Understanding these complex mechanisms is key for effective PD-1 blockade cancer therapy.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Programmed death ligand-1 (PD-L1) expression is a complex process crucial for understanding PD-1 blockade therapy efficacy.
- The specific mechanisms of PD-L1 expression in oral squamous cell carcinomas (OSCCs) remain incompletely understood.
- Investigating PD-L1 regulation offers potential for optimizing cancer treatment strategies.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating PD-L1 expression in OSCC.
- To examine the roles of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling pathways in PD-L1 upregulation.
- To correlate in vivo phosphorylation patterns with PD-L1 expression and tumor microenvironment features.
Main Methods:
- In vitro studies using OSCC cell lines with immunoblotting to analyze signaling pathways.
- In vivo analysis using multi-fluorescence immunohistochemistry (MF-IHC) on tumor tissues.
- Focus on phosphorylation of downstream molecules in EGF and IFN-γ signaling cascades.
Main Results:
- In vitro: EGF upregulates PD-L1 via EGFR/PI3K/AKT, EGFR/STAT1, and EGFR/MEK/ERK pathways.
- In vitro: IFN-γ upregulates PD-L1 via JAK2/STAT1 pathway.
- In vivo: STAT1 and EGFR phosphorylation are frequent in PD-L1-positive OSCC; STAT1 phosphorylation correlates with lymphocyte infiltration and EGFR phosphorylation.
Conclusions:
- PD-L1 expression mechanisms in OSCC are multifaceted and influenced by signaling pathways like EGF and IFN-γ.
- The phosphorylation patterns of key molecules (STAT1, EGFR) vary, indicating distinct regulatory mechanisms.
- Tailoring PD-1 blockade therapy requires considering individual tumor microenvironments and molecular alterations affecting PD-L1 expression.
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