The prognostic value of immune checkpoints in oral squamous cell carcinoma

Abstract Background: Despite the importance of immune checkpoints in immunotherapy, the prognostic value of these molecules remains controversial in oral squamous cell carcinoma (OSCC). We performed a systematic review to investigate the prognostic significance of the immune checkpoints in OSCC. Materials: A systematic search was conducted in Ovid Medline, Scopus and Cochrane libraries, and all studies that evaluated the prognostic significance of immune checkpoints in OSCC were systematically retrieved. Results: Twelve immune checkpoints/modulators were studied for their prognostic values in OSCC patients between 1985 and 2017. Seven immune checkpoints (FKBP51, B7‐H4, B7‐H6, ALHD1, PD‐L1, B7‐H3 and IDO1) were reported to be associated with poor patients’ survival in at least one study, and five (CTLA‐4, TLT‐2, VISTA, PD‐L2 and PD‐1) did not have a significant prognostic value. PD‐L1 results were controversial as it was reported to be associated with both better and worse patients’ survival. Conclusions: Even though immune checkpoint markers had high expectation for OSCC prognostication, our systematic review revealed that the majority of them had been studied only once. The other molecules, which had been studied more than once, had controversial findings, except B7‐H3

Evaluation of in vitro and in vivo personalized cancer treatment assays for oral squamous cell carcinoma

Abstract Background: Oral squamous cell carcinoma (OSCC) is a common cancer with a high heterogeneity and few approved treatments. OSCC is one of the least explored areas for precision oncology. In this study, we aimed to test the reliability of our three established rapid cancer systemic treatment-testing assays: human tumour-derived matrix (Myogel)-coated well-plates, zebrafish xenografts, and 3D microfluidic chips. Methods: Chemo-, radio- and targeted-therapy testing in Myogel-coated wells and zebrafish xenografts was conducted nine times using five samples; two primary and three metastatic lymph node samples from three OSCC patients. Peripheral blood mononuclear cells (PBMNCs) were isolated from the patients’ blood. The response of the tumour cells to radio-, chemo-, and targeted therapy was tested using Myogel-coated wells and zebrafish larvae xenografts. The tumour cells’ response to immunotherapy was tested using 3D microfluidic chips. The cells’ sensitivity to the treatments was compared with the patients’ clinical response. Primary and metastatic lymph node tissue-derived DNA samples from two patients underwent whole exome sequencing to compare the mutational profiles of the samples. Results: Test results were in line with patients’ responses in 7/9 (77%) zebrafish xenograft assays and 5/9 (55%) Myogel-coated wells assays. Immunotherapy testing was done using one metastatic patient sample which matched the patients’ response. Differences in responses to treatments between primary and metastatic samples of the same patient were detected in 50% of the zebrafish larvae assays. Conclusions: Our results show the potential of using personalized cancer treatment testing assays — specifically zebrafish xenografts that revealed promising results — in OSCC patient samples

Immune checkpoints indoleamine 2,3‐dioxygenase 1 and programmed death‐ligand 1 in oral mucosal dysplasia

Abstract Background: Oral mucosal dysplasia is a histologic feature of potentially malignant disorders that is associated with the risk of transformation to carcinoma. Dysplastic cells use many strategies during their transformation to cancer, including escape from the immune mediated destruction. We hypothesized that adaptive immunity is inhibited by activation of distinct immune checkpoint molecules, such as indoleamine 2,3‐dioxygenase 1 (IDO1) and programmed death‐ligand 1 (PD‐L1). Methods: We collected 63 oral dysplasia samples from 47 patients. Nine biopsies from alveolar mucosa were taken during wisdom teeth extractions were used as healthy controls. Tissue samples were stained and scored for IDO1 and PD‐L1. Additionally, dysplasia grades and inflammatory cell infiltration were evaluated. Eight patients were followed up to 36 months to evaluate dysplasia progression, inflammation, and immune checkpoint molecules expression. Results: Dysplastic epithelium had significantly lower IDO1 expression than that of healthy controls. PD‐L1 positive cells in the lamina propria were mainly in dysplastic samples and seldom in healthy controls. Dysplasia grade was associated negatively with epithelium IDO1 and positively with IDO1 and PD‐L1 expression in the lamina propria. There was a positive association between dysplasia grade and level of inflammatory cell infiltration. During follow‐up, dysplasia grade, inflammatory cell infiltration, and the immune checkpoint expression fluctuated over time. Conclusions: Immune checkpoint molecules IDO1 and PD‐L1 are modulated during oral epithelial dysplastic changes, and their expression is associated with inflammatory cell infiltration in the lamina propria. As immune checkpoint molecules expression fluctuates over time, these molecules are not useful as biomarkers for oral mucosal dysplasia progression