Abstract
Head and neck squamous cell carcinoma (HNSCC) ranks among the top most common cancers with a poor prognosis. The mechanism of chemoresistance is still not well known. This study is to investigate the programmed death‐ligand 1 (PD‐L1) expression in HNSCC, and test the effect of lactoferricin B (LfcinB) on chemoresistance and its mechanism. We analyzed 510 HNSCC patients in TCGA database and investigated how CD274 expression was related to patient prognosis. PD‐L1 was verified from HNSCC samples at local hospital with immunohistochemistry. PD‐L1 expression in the acquired cisplatin‐resistant HNSCC cells was examined by PCR and WB in order to test PD‐L1‐induced chemoresistance. LfcinB inoculation in cisplatin‐resistant HNSCC cells and in the nude mice was introduced to test the effect of LfcinB on targeting cisplatin resistance and its mechanism. High CD274 mRNA (>125 FPKM) from TCGA database had a significantly reduced 5‐year survival rate, and a lower 5‐year survival rate in the chemotherapy and radiotherapy‐treated patients (P < .05). PD‐L1 overexpression was further supported from analysis of 40 HNSCC specimens. PD‐L1 and IL‐6 in the established cisplatin‐resistant HNSCC cells were shown significantly higher (P < .05). IL‐6 and PD‐L1 expression were partially inhibited by the anti‐IL‐6/STAT3 antibody. LfcinB displayed a direct cytotoxic effect on cisplatin‐resistant HNSCC cells and HNSCC xenografts of cisplatin‐resistant cells in the nude mice displayed significant reduction in tumor volume after LfcinB injection (P < .05). Besides, the increase of IL‐6 and PD‐L1 in cisplatin‐resistant HNSCC cells was abolished in vitro by LfcinB (P < .05). PD‐L1 expression in HNSCC cells correlates with poor prognosis and chemoresistance, and LfcinB might provide therapeutic potential in HNSCC patients through modulating IL‐6 and PD‐L1.
Highlights
Head and neck cancer ranks among the top most common cancers worldwide and head and neck squamous cell carcinoma (HNSCC) accounts for nearly 90% of head and neck cancer with a number of 644 000 cases are diagnosed worldwide each year.[1]
PD-1/PD-L 1 mediated immune suppression in T-cell immune suppression and the potential for immunotherapy via blocking programmed death-ligand 1 (PD-L1)/PD-1 was highlighted in HNSCC.[5,6]
Our analysis of PD-L 1 positivity from the cancer genomic atlas (TCGA) cohort and HNSCC specimens from the local hospital was above 90%, which is in agreement with the reported data (70%-9 0%) in HNSCC,[17-19] while the positivity from HNSCC was shown much higher than melanoma, and the other malignancies.[20,21]
Summary
Head and neck cancer ranks among the top most common cancers worldwide and head and neck squamous cell carcinoma (HNSCC) accounts for nearly 90% of head and neck cancer with a number of 644 000 cases are diagnosed worldwide each year.[1]. The previous work demonstrated that the increased expression of interleukin 6 (IL-6 ) is associated with poor prognosis and cisplatin- acquired chemoresistance of HNSCC4 while the mechanism of chemoresistance is still not clear. As LfcinB was tested for the cytotoxic effect against the oral cavity squamous cell carcinoma and HNSCC cells,[11,12] LfcinB may offer hope to break down the chemoresistance of HNSCC while further investigations focused on mechanism are needed. In order to examine PD-L 1 induced cisplatin resistance, we tested cisplatin sensitivity and PD-L1 expression in the acquired cisplatin-resistant HNSCC cell lines. In vitro inoculation of LfcinB in cisplatin- resistant HNSCC cells and in vivo local injection of LfcinB into the implanted HNSCC tumor in the nude mice were introduced to test the effect of LfcinB on targeting cisplatin resistance and its mechanism
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