In Situ PD-L1 Expression in Oral Squamous Cell Carcinoma Is Induced by Heterogeneous Mechanisms among Patients

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.

Establishment of Mucoepidermoid Carcinoma Cell Lines from Surgical and Recurrence Biopsy Specimens

“…The accumulation of gene alterations produced by clonal evolution could result in a cetuximab-resistant MEC clone. Our previous study showed that EGFR signaling in OSCCs reduces effector T-cell infiltration and increases Treg, generating an immunosuppressive tumor microenvironment similar to that observed in non-small cell lung cancers [ 30 , 31 ]. Future investigations should focus on the influence of EGFR signaling blockade on tumor immunity and survival using the MEC cell lines.…”

Mechanism of Wuyao–Ginseng Medicine Pair in the Prevention and Treatment of Diarrhea-Type Irritable Bowel Syndrome Based on Gene Expression Omnibus Chip Data

“…An overexpression of NCOA2 in mouse prostate tumors led to the overactivation of PI3K/AKT and MAPK signals, thus promoting the tumor malignancy [ 24 ]. The epidermal growth factor upregulated the PD-L1 expression in OSCC cell lines through the epidermal growth factor receptor (EGFR)/PI3K/AKT pathway [ 25 ]. Ginsenoside compound K inhibited the proliferation, migration, and invasion of Eca109 cells through the VEGFA/Pi3k/Akt pathway [ 26 ].…”

Molecular basis, potential biomarkers, and future prospects of OSCC and PD-1/PD-L1 related immunotherapy methods

“…The phosphorylation patterns of related molecules differ among patients. This suggests that different tissue microenvironments affect the expression of PD-L1, it is essential to design appropriate PD-1 blockade combination therapy regimens for each patient during any treatment and research programs [ 78 ].…”