Prognostic value of tumor-infiltrating immune cells in clinical early-stage oral squamous cell carcinoma.

BACKGROUND: Tumor-infiltrating immune cells (TIICs) are critical components of tumor immune microenvironment (TIME), which play crucial roles during tumor initiation, development, and progression. However, the prognostic value of TIICs is still not well documented in clinical early-stage oral squamous cell carcinoma (OSCC). In this study, we aimed to assess the prognostic value of TIICs in clinical early-stage OSCC and develop a nomogram based on TIICs to predict the prognosis. METHODS: Eighty patients with clinical early-stage (cT1,2N0M0) OSCC were enrolled in this study. Immunohistochemical staining was performed to evaluate the infiltration of TIICs, including CD8+ T cells, CD57+ NK cells, CD163+ macrophage, and CD20+ B cells. Overall survival (OS) and disease-free survival (DFS) curves were plotted by the Kaplan-Meier method. Cox's proportional hazards regression models were performed to assess the prognostic value of TIICs. Finally, a nomogram was established to predict the OS based on TIICs infiltration and assessed by concordance index (C-index) and calibration curve. RESULTS: High infiltrations of CD57+ NK cells and CD20+ B cells indicated a better OS in clinical early-stage OSCC. Moreover, high infiltration of CD20+ B cells favored a longer DFS. Of note, low infiltrations of CD57+ NK cells and CD20+ B cells were independent prognostic factors for poor OS in clinical early-stage OSCC. The nomogram that combined CD57+ NK cells with CD20+ B cells could predict the OS in clinical early-stage OSCC, and the C-index was 0.801 (95% CI: 0.679-0.924). The calibration plot showed that prediction and observation are well matched. CONCLUSIONS: High infiltration of CD57+ NK cells and CD20+ B cells indicate a favorable OS in clinical early-stage OSCC. The nomogram constructed based on TIICs might be used for predicting the prognosis in clinical early-stage OSCC.

BET inhibition triggers antitumor immunity by enhancing MHC class I expression in head and neck squamous cell carcinoma.

BET inhibition has been shown to have a promising antitumor effect in multiple tumors. However, the impact of BET inhibition on antitumor immunity was still not well documented in HNSCC. In this study, we aim to assess the functional role of BET inhibition in antitumor immunity and clarify its mechanism. We show that BRD4 is highly expressed in HNSCC and inversely correlated with the infiltration of CD8+ T cells. BET inhibition potentiates CD8+ T cell-based antitumor immunity in vitro and in vivo. Mechanistically, BRD4 acts as a transcriptional suppressor and represses the expression of MHC class I molecules by recruiting G9a. Pharmacological inhibition or genetic depletion of BRD4 potently increases the expression of MHC class I molecules in the absence and presence of IFN-γ. Moreover, compared to PD-1 blocking antibody treatment or JQ1 treatment individually, the combination of BET inhibition with anti-PD-1 antibody treatment significantly enhances the antitumor response in HNSCC. Taken together, our data unveil a novel mechanism by which BET inhibition potentiates antitumor immunity via promoting the expression of MHC class I molecules and provides a rationale for the combination of ICBs with BET inhibitors for HNSCC treatment.

Prognostic value of tertiary lymphoid structures in early clinical stage oral tongue squamous cell carcinoma.

BACKGROUND: Tertiary lymphoid structures have been observed in several solid tumors and suggested to be a favorable prognostic factor. However, the prognostic value of tertiary lymphoid structures for early clinical stage (cT1/2N0) oral tongue squamous cell carcinoma (OTSCC) remains unclear. In this study, we aimed to evaluate the prognostic value of tertiary lymphoid structures in cT1/2N0 stage OTSCC. METHODS: Ninety-seven patients with cT1/2N0 stage OTSCC were enrolled in this study. Tertiary lymphoid structures were assessed in paraffin sections with H.E and immunohistochemistry staining. Overall and disease-free survivals were evaluated by the Kaplan-Meier method. Cox proportional hazards regression models were used to assess their prognostic value. RESULTS: Tertiary lymphoid structures can be readily identified in cT1/2N0 stage OTSCC, including early tertiary lymphoid structures, primary follicle-like tertiary lymphoid structures, and secondary follicle-like tertiary lymphoid structures. Its frequency in OTSCC was 76.3% in the cohort. The presence of tertiary lymphoid structures was associated with favorable overall survival (p = 0.0176) and disease-free survival (p = 0.0183) in early clinical stage OTSCC. Cox regression models showed that tertiary lymphoid structures can serve as an independent prognostic factor for overall survival (HR = 0.434, 95% CI = 0.212-0.886, p = 0.022) and disease-free survival (HR = 0.459, 95% CI = 0.235-0.897, p = 0.023) in early clinical stage OTSCC. The group of low maturity of TLS combined with pN positive had the lowest overall survival (p = 0.0094) and disease-free survival (p = 0.0028). CONCLUSIONS: Tertiary lymphoid structures are frequently observed in OTSCC. It is associated with a favorable prognosis for patients with cT1/2N0 stage OTSCC and may be used to predict immunotherapy sensitivity.

The prognostic role of tumour-infiltrating lymphocytes in oral squamous cell carcinoma: A meta-analysis.

It has been suggested that tumour-infiltrating lymphocytes (TILs) are associated with the progression of oral squamous cell carcinoma (OSCC). However, the prognostic value of TILs is inconclusive due to the heterogeneity of immune cells within the tumour microenvironment. In this meta-analysis, we aimed to assess the prognostic value of TILs in OSCC. The PubMed, Cochrane, Embase, Scopus and Web of Science databases were searched up to April 20, 2019, and 33 studies were ultimately included in this meta-analysis. Our pooled meta-analysis showed that high infiltration of CD8+ TILs, CD45RO+ TILs and CD57+ TILs favoured better overall survival (OS). However, high infiltration of CD68+ macrophages and CD163+ macrophages was associated with poor prognosis in OSCC. These findings suggest that CD8+ TILs, CD45RO+ TILs, CD57+ TILs, CD68+ macrophages and CD163+ macrophages might serve as novel prognostic factors and therapeutic targets in OSCC.

A Super-Enhancer Driven by FOSL1 Controls miR-21-5p Expression in Head and Neck Squamous Cell Carcinoma.

MiR-21-5p is one of the most common oncogenic miRNAs that is upregulated in many solid cancers by inhibiting its target genes at the posttranscriptional level. However, the upstream regulatory mechanisms of miR-21-5p are still not well documented in cancers. Here, we identify a super-enhancer associated with the MIR21 gene (MIR21-SE) by analyzing the MIR21 genomic regulatory landscape in head and neck squamous cell carcinoma (HNSCC). We show that the MIR21-SE regulates miR-21-5p expression in different HNSCC cell lines and disruption of MIR21-SE inhibits miR-21-5p expression. We also identified that a key transcription factor, FOSL1 directly controls miR-21-5p expression by interacting with the MIR21-SE in HNSCC. Moreover, functional studies indicate that restoration of miR-21-5p partially abrogates FOSL1 depletion-mediated inhibition of cell proliferation and invasion. Clinical studies confirmed that miR-21-5p expression is positively correlated with FOSL1 expression. These findings suggest that FOSL1-SE drives miR-21-5p expression to promote malignant progression of HNSCC.

Prognostic value of epithelial-mesenchymal transition-inducing transcription factors in head and neck squamous cell carcinoma: A meta-analysis.

Epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression and is primarily regulated by several EMT-inducing transcription factors (EMT-TFs), including TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, and ZEB2. However, the prognostic value of EMT-TFs remains controversial in head and neck squamous cell carcinoma (HNSCC). Studies on the prognostic role of EMT-TFs in HNSCC were searched for in the Web of Science, Science Direct, Proquest, EMBASE, PubMed, and Cochrane Library. Meta-analysis was performed by using Revman 5.2 software. The pooled analysis showed that overexpression of EMT-TFs indicated a poor overall survival (OS) (HR = 1.93, 95% CI = 1.67-2.23) of HNSCC. Subgroup analysis for individual EMT-TFs revealed that overexpression of TWIST1 (HR = 1.61, 95% CI = 1.29-2.02), SNAI1 (HR = 2.17, 95% CI = 1.63-2.88), SNAI2 (HR = 1.90, 95% CI = 1.38-2.62), and ZEB1 (HR = 2.70, 95% CI = 1.61-4.53) were significantly associated with poor OS of HNSCC. These findings support the hypothesis that overexpression of EMT-TFs indicates a poor prognosis for HNSCC patients.

Potential Role of lncRNA H19 as a Cancer Biomarker in Human Cancers Detection and Diagnosis: A Pooled Analysis Based on 1585 Subjects.

Long noncoding RNAs (lncRNAs) have been reported to serve as diagnostic and prognostic biomarkers of cancers, which play vital roles in tumorigenesis and tumor progression. Several studies have been performed to explore diagnostic value of lncRNA H19 in cancer detection and diagnosis. However, there are still inconsistent results in diagnostic accuracy and reliability in individual studies. Therefore, the present study was performed to summarize the overall diagnostic performance of lncRNA H19 in cancer detection and diagnosis. A total of eight studies with 770 cases and 815 controls were included in this pooled analysis. The pooled diagnostic results were as follows: sensitivity, 0.69 (95%CI=0.62-0.76), specificity, 0.79 (95% CI=0.70-0.86), positive likelihood ratio (PLR), 3.31 (95%CI=2.29-4.78), negative likelihood (NLR), 0.39 (95%CI=0.31-0.49), diagnostic odds ratio (DOR), 8.53 (95%CI=4.99-14.60), and area under the curve (AUC), 0.79 (95%CI=0.76-0.83). Deeks' funnel plot asymmetry test (P=0.13) suggested no potential publication bias. Our results indicated that lncRNA H19 had a relatively moderate accuracy in cancer detection and diagnosis. Further comprehensive prospective studies with large sample sizes are urgently required to validate our findings.