Proceedings on Cancer-Immuno-Oncology
Vol. 1 No. 1 (2018): Proceedings on Cancer-Immuno-Oncology
https://doi.org/10.18416/CIO.2018.1810047
Effects of EGFR-MEK-ERK pathway on PD-L1 expression in head and neck squamous cell carcinoma
Main Article Content
Copyright (c) 2018 Bohai Feng, Chao Rong, Marie Muller, Dana Holzinger, Christa Flechtenmacher, Julia Thierauf, Annette Affolter, Peter Plinkert, Jochen Hess
This work is licensed under a Creative Commons Attribution 4.0 International License.
Abstract
Objectives: Programmed death ligand-1 (PD-L1) is frequently expressed in human cancers, including head and neck squamous cell carcinoma (HNSCC). However, the regulation of PD-L1 in HNSCC remains largely elusive. The purpose of this study was to address the molecular mechanism of PD-L1 regulation by EGFR-MEK-ERK signaling and to suggest potential clinical relevance of blocking PD-1/PD-L1 in combination with therapeutic options targeting EGFR signaling in HNSCC.
Methods: Correlations of PD-L1 protein expression and key nodes of EGFR-MEK-ERK signaling in HNSCC were analyzed by The Cancer Proteome Atlas (TCPA, http://tcpaportal.org). The impact of drugs targeting the EGFR-MEK-ERK pathway on tumor cell survival, clonal expansion as well as PD-L1 expression were addressed in cell culture models. PD-L1 expression and ERK1/2 phosphorylation (p-ERK1/2) were assessed on tissue microarrays with specimens from primary oropharyngeal squamous cell carcinoma (OPSCC) (n=123 patients) by immunohistochemistry and were compared with clinic-pathological features.
Results: A highly significant association was found between PD-L1 expression and key nodes of EGFR-MEK-ERK signaling analyzing the TCPA-HNSCC dataset. However, no significant association was found between PD-L1 expression and p-ERK1/2 protein level in the TCPA-HNSCC dataset OPSCC cohort. The impact of cetuximab on PD-L1 expression in HNSCC cell lines after short-term or long-term treatment was heterogeneous but independent of ERK1/2 phosphorylation. Treatment with a MEK1/2 inhibitor confirmed that PD-L1 regulation in HNSCC cell lines is largely independent of MEK-ERK signaling. The majority of HNSCC cell lines with long-term cetuximab treatment regained ERK1/2 phosphorylation as compared to short-term treatment. Up-regulation of PD-L1 was observed in most cetuximab-resistant cell lines after long-term treatment.
Conclusion: Our findings suggest a complex and context-dependent PD-L1 regulation upon inhibition of the EGFR-MEK-MAPK signaling cascade and further experimental and clinical studies will be essential to unravel underlying molecular principles.