Acidity in the tumor microenvironment has been reported to promote cancer growth and metastasis. In our study, we examined a potential relation between extracellular acidity and expression level of the immune checkpoint molecule programmed cell death protein 1 (PD-L1) in murine squamous cell carcinoma (SCC) and melanoma cell lines. PD-L1 expression in the tumor cells was upregulated by culturing in a low pH culture medium. Tumor-bearing mice were allowed to ingest sodium bicarbonate, resulting in neutralization of acidity in the tumor tissue, a decrease in PD-L1 expression in tumor cells and suppression of tumor growth in vivo. Proton-sensing G protein-coupled receptors, T-cell death-associated gene 8 (TDAG8) and ovarian cancer G-protein-coupled receptor 1 (OGR1), were upregulated by low pH, and essentially involved in the acidityinduced elevation of PD-L1 expression in the tumor cells. Human head and neck SCC RNAseq data from the Cancer Genome Atlas also suggested a statistically significant correlation between expression levels of the proton sensors and PD-L1 mRNA expression.These findings strongly suggest that neutralization of acidity in tumor tissue may result in reduction of PD-L1 expression, potentially leading to inhibition of an immune checkpoint and augmentation of antitumor immunity.
Laryngeal granuloma is an uncommon complication of prolonged endotracheal intubation. A 25-year-old woman with severe jaw deformity underwent sagittal split ramus osteotomy under general anesthesia. Two days after extubation, the patient complained of hoarseness, sore throat, and dyspnea. When symptoms persisted, she was evaluated in the Otolaryngology Department. She was diagnosed with laryngeal granuloma of the bilateral arytenoid cartilages, and conservative treatment was selected. Administration of corticosteroid hormones, proton pump inhibitors, and a subsequent follow-up examination performed in our outpatient clinic showed no evidence of recurrence 10 months after the initial presentation.
Several clinical trials are ongoing to evaluate induction chemotherapy and immunotherapy for locally advanced head and neck squamous cell carcinoma (HNSCC) including oral cancer, with the aim of improving survival and functional outcomes. Our tumor-immune microenvironmental analyses based on multiplex immunohistochemistry and image cytometry revealed the presence of three types of immune characteristics, which were associated with the efficacy of induction chemotherapy in locally advanced HNSCC. Tissue biomarker-guided patient selection can optimize future treatment strategies including induction chemotherapy/immunotherapy and surgical procedures in oral cancer.
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