Cisplatin‐induced programmed cell death ligand‐2 expression is associated with metastasis ability in oral squamous cell carcinoma

Abstract

Programmed cell death ligands (PD-Ls) are expressed in tumor cells where they bind to programmed cell death-1, an immunocyte co-receptor, resulting in tumor cell evasion from the immune system. Chemotherapeutic drugs have been recently reported to induce the expression of PD-L, such as PD-L1, in some cancer cells. However, little is known regarding PD-L2 expression and its role in oral squamous cell carcinoma (OSCC). In this study, we examined the effect of cisplatin on the expression and regulation of PD-L2 in OSCC cell lines and analyzed malignant behavior in PD-L2-expressing cells using colony, transwell and transformation assays. In addition, we examined PD-L2 expression in the tumor tissues of OSCC patients using cytology and tissue microarray methods. In OSCC cell lines, cisplatin treatment upregulated PD-L2 expression, along with that of the drug efflux transporter ABCG2, via signal transducers and activator of transcription (STAT) 1/3 activation. Moreover, PD-L2positive or PD-L2-overexpressing cells demonstrated upregulation in both invasion and transformation ability but not in proliferation compared with PD-L2-negative or PD-L2-silencing cells. PD-L2 expression was also observed in OSCC cells of cytology samples and tissue from OSCC patients. The intensity of PD-L2 expression was correlated with more malignant morphological features in the histological appearance and an invasive pattern. Our findings indicate that cisplatin-upregulated PD-L2 expression in OSCC via STAT1/3 activation and the expression of PD-L2 are likely to be associated with malignancy in OSCC. The PD-L2 expression in cisplatin-resistant OSCC cells may be a critical factor in prognosis of advanced OSCC patients.

PD‐L1 and PD‐L2 expression status in relation to chemotherapy in primary and metastatic esophageal squamous cell carcinoma

“…The EGFR and JAK/STAT pathways have been reported to play a crucial role in the regulation of PD‐L1/L2 expression, and several studies have shown that these pathways are influenced by CDDP or 5‐FU treatment. 14 , 15 , 24 , 25 Thus, we examined EGFR and JAK/STAT pathway proteins in cell lines with decreased PD‐L2 in response to CDDP (TE‐1 and TE‐10) and those with increased PD‐L2 in response to CDDP (TE‐9 and KYSE30; Figure 3A ). We found that pSTAT1/3 was decreased in TE‐1 and TE‐10 cells treated with CDDP, while pSTAT1/3 was increased in TE‐9 and KYSE30 cells incubated with CDDP.…”

“… 11 , 12 , 13 In contrast, only a few reports have examined the effect of these treatments on PD‐L2. 14 , 15 Given the efforts to develop combination treatments of ICIs with conventional chemotherapeutic drugs, 16 , 17 , 18 clarifying the change of PD‐L1/L2 expression in response to chemotherapy is clinically important.…”

The Molecular Basis and Therapeutic Aspects of Cisplatin Resistance in Oral Squamous Cell Carcinoma

“…Sudo, et al established a cisplatin-resistant OSCC cell line, HSC-2, and found that cisplatin upregulated the gene expression levels of PD-L2, ABCG2 in HSC-2 in a time-dependent manner. In addition, STAT1/3 mediated the induction of PD-L2 by cisplatin, and PD-L2-positive cells have higher metastatic and invasive potential compared to PD-L2-negative cells (97). These studies suggested that anti-PD-L immunotherapy may be valuable for cisplatin-resistant OSCC patients.…”

Transcutaneous Carbon Dioxide Decreases Immunosuppressive Factors in Squamous Cell Carcinoma In Vivo

“…There are also research reports showing increased PD-L1 expression with platinum treatment in other tumours [ 36 , 37 ]. Sudo et al reported that cisplatin also increased PD-L2 expression in oral squamous cell carcinoma cell lines [ 38 ]. However, no significant change in PD-L1 expression was observed in the chemosensitive cells [ 13 ].…”