Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment
Mariko Hirai1, Hiroko Kitahara1, Yutaka Kobayashi1
1Department of Oral and Maxillofacial Surgery, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa 920-8640, Japan.
Abstract:
Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expression has been proposed as a potential mechanism responsible for this phenotype. Despite the fact that anti-PD-1 treatment can produce durable responses, such therapy appears to benefit only a subset of patients. Thus, it is important to understand the mechanisms underlying regulation of PD-L1 expression in the OSCC microenvironment. In this study, we showed that PD-L1 expression in high-grade invasive OSCC cell lines was lower than that in a low-grade invasive OSCC line and found a close correlation between PD-L1 expression and the epithelial-mesenchymal transition (EMT). PD-L1 expression was upregulated in macrophages and dendritic cells (DCs) in high-grade invasive human OSCC tissues or co-cultured with mesenchymal-phenotype OSCC cells in vitro. TLR4-inhibitory peptide successfully suppressed PD-L1 upregulation on macrophages and DCs co-cultured with mesenchymal-phenotype OSCC cells, suggesting that some EMT-induced tumour antigen is critical for PD-L1 induction on tumour-associated macrophages and DCs. Further studies are necessary to explore the impact of EMT on the tumour immune microenvironment and to identify potential biomarkers for selecting patients who might preferentially benefit from PD-1/PD-L1 blockade or immunotherapies more broadly.
Insights
Blockade of programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) shows promise in cancer treatment. In oral squamous cell carcinoma (OSCC), PD-L1 expression correlates with epithelial-mesenchymal transition (EMT), impacting the tumor immune microenvironment.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- The programmed cell death 1 (PD-1)/programmed cell death ligand (PD-L1) pathway is a key regulator of the immune response and a target for cancer immunotherapy.
- Oral squamous cell carcinoma (OSCC) exhibits immunosuppressive properties, potentially mediated by PD-L1 expression.
- While PD-1/PD-L1 blockade offers durable responses in some patients, understanding the regulation of PD-L1 in OSCC is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the relationship between PD-L1 expression and the epithelial-mesenchymal transition (EMT) in oral squamous cell carcinoma (OSCC).
- To elucidate the mechanisms regulating PD-L1 expression in the OSCC tumor microenvironment, particularly on immune cells.
- To identify potential biomarkers for patient selection in PD-1/PD-L1 blockade therapy.
Main Methods:
- Comparative analysis of PD-L1 expression in different grades of OSCC cell lines.
- In vitro co-culture experiments with OSCC cells and immune cells (macrophages, dendritic cells).
- Assessment of PD-L1 upregulation on immune cells in response to OSCC cells and treatment with TLR4-inhibitory peptide.
Main Results:
- PD-L1 expression was inversely correlated with the grade of invasiveness in OSCC cell lines.
- A strong correlation was observed between PD-L1 expression and the epithelial-mesenchymal transition (EMT) phenotype in OSCC.
- PD-L1 was upregulated on macrophages and dendritic cells (DCs) when co-cultured with mesenchymal-phenotype OSCC cells.
- TLR4-inhibitory peptide treatment suppressed PD-L1 upregulation on macrophages and DCs, suggesting a role for EMT-induced antigens.
Conclusions:
- EMT plays a significant role in regulating PD-L1 expression in OSCC, influencing the tumor immune microenvironment.
- EMT-induced tumor antigens may be critical for PD-L1 induction on tumor-associated macrophages and DCs.
- Further research into the impact of EMT on immune responses and the identification of predictive biomarkers is warranted for effective PD-1/PD-L1 blockade therapy in OSCC.
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