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Buparlisib modulates PD-L1 expression in head and neck squamous cell carcinoma cell lines
Mathias Fiedler1, Daniela Schulz1, Gerhard Piendl2
1Department of Oral and Maxillofacial Surgery and Center for Medical Biotechnology, University Hospital Regensburg, 93053, Regensburg, Germany.
Abstract:
High expression of the immune checkpoint receptor PD-L1 is associated with worse patient outcome in a variety of human cancers, including head and neck squamous cell carcinoma (HNSCC). Binding of PD-L1 with its partner PD-1 generates an inhibitory signal that dampens the immune system. Immunotherapy, that is blocking the PD-1/PD-L1 checkpoint, has proven to be an effective tool in cancer therapy. However, not all patients are able to benefit from this immune checkpoint inhibition. Therefore, evidence is growing of intrinsic PD-L1 signaling in cancer cells. For example, intrinsic PD-L1 expression was associated with PI3K/Akt/mTOR signaling, which is part of diverse oncogenic processes including cell proliferation, growth and survival. In this study we demonstrate the effects of PI3K/Akt/mTOR pathway inhibition by buparlisib on PD-L1 expression in HNSCC cell lines. After buparlisib treatment for 72 h, PD-L1 was downregulated in total cell lysates of HNSCC cells. Moreover, flow cytometry revealed a downregulation of PD-L1 membrane expression. Interestingly, the buparlisib mediated effects on PD-L1 expression were reduced by additional irradiation. In PD-L1 overexpressing cells, the buparlisib induced inhibition of proliferation was neutralized. In summary, our findings imply that blocking the PI3K/Akt/mTOR pathway could be a good additional therapy for patients who show poor response to immune checkpoint therapy.
Insights
Blocking the PI3K/Akt/mTOR pathway with buparlisib downregulates PD-L1 expression in head and neck squamous cell carcinoma (HNSCC) cells. This suggests a potential new therapy for patients unresponsive to current immune checkpoint inhibitors.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- High programmed death-ligand 1 (PD-L1) expression correlates with poor outcomes in head and neck squamous cell carcinoma (HNSCC).
- Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway are effective but not universally beneficial.
- Intrinsic PD-L1 signaling in cancer cells, linked to PI3K/Akt/mTOR pathways, contributes to oncogenesis.
Purpose of the Study:
- To investigate the impact of PI3K/Akt/mTOR pathway inhibition using buparlisib on PD-L1 expression in HNSCC.
- To evaluate the combined effects of buparlisib and irradiation on PD-L1 expression and cell proliferation in HNSCC.
Main Methods:
- Treatment of HNSCC cell lines with buparlisib for 72 hours.
- Analysis of PD-L1 expression in total cell lysates and on the cell membrane via flow cytometry.
- Assessment of PD-L1 expression and cell proliferation under combined buparlisib and irradiation treatment.
Main Results:
- Buparlisib treatment significantly downregulated PD-L1 expression in HNSCC cells, both in total lysates and on the cell membrane.
- Concurrent irradiation reduced the buparlisib-mediated downregulation of PD-L1.
- In PD-L1 overexpressing cells, buparlisib's anti-proliferative effect was counteracted by additional irradiation.
Conclusions:
- Inhibition of the PI3K/Akt/mTOR pathway effectively reduces PD-L1 expression in HNSCC.
- Combining PI3K/Akt/mTOR inhibition with irradiation may modulate PD-L1 levels and impact treatment efficacy.
- Targeting the PI3K/Akt/mTOR pathway represents a promising strategy to enhance responses to immune checkpoint therapy in HNSCC patients.
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