The prognostic value of tumor-infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) remains controversial. Additionally, there is no standardized approach or cutoff value for evaluating TIL levels. The aim of this study was to establish a feasible method and criterion to assess TIL levels for future clinical practice and research use and to explore the relationship between TIL levels and prognosis. This retrospective cohort study reviewed the records and pathological sections of 202 patients with HNSCC who were surgically treated at Beijing Stomatological Hospital, Capital Medical University, from January 1998 to January 2011. The predictor variable was the TIL level. The main outcome assessment parameters were disease-free survival (DFS) and disease-specific survival (DSS). The T stage (P = .008), smoking history (P = .042), alcohol history (P = .048), need for radiotherapy (P = .012) and microscopic extracapsular spread (ECS) (P = .012) were associated with the TIL level. A cutoff value equal to 70% could be taken as a threshold for TIL assessment, with a TIL level higher than 70% associated with a better prognosis (DFS rate: 51.9%, P = .018; DSS rate: 59.3%, P = .049). The Cox regression model showed that the TIL level was an independent prognostic factor for DFS (hazard ratio (HR): 0.786, 95% CI: 0.618-0.999, P = .049). The TIL level is closely related to the prognosis of patients with HNSCC. A threshold value of 70% is appropriate for TIL assessment, as patients with a TIL level higher than 70% show a better prognosis. Thus, the TIL level might serve as an independent predictor for HNSCC recurrence.

The lymph node ratio(LNR) has been described as a novel predictor of the survival of patients with oral and oropharyngeal squamous cell carcinoma(O/OPSCC). The purpose of this study was to evaluate whether LNR is better at predicting survival and the need for adjuvant treatment than traditional tumour-nodal-metastasis(TNM) staging. Eight hundred nine patients with O/OPSCC and positive lymph node disease were retrospectively enrolled in this study. LNR equal to 0.075 is the best cut-off value for stratifying 5-year disease-free survival(DFS). High LNR is closely associated with more advanced T stage, higher N stage, more severe pathological grade, the presence of diffuse infiltration and extracapsular spread(ECS). LNR is better for evaluating prognosis than the pathological N stage. Patients with high LNR coupled with high number of positive lymph nodes who received adjuvant concurrent chemo-radiotherapy(CCRT) had a better 5-year DFS than patients who received surgery alone. Multivariate analyses revealed that T stage, ECS and LNR are independent prognostic factors of 5-year DFS and disease-specific survival(DSS). Therefore, high LNR is closely correlated with adverse parameters that markedly hinder prognosis. LNR is superior to traditional TNM staging for the evaluation of prognosis,and the combination of the LNR with the number of positive lymph nodes can predict the benefits of adjuvant CCRT.

The tumor margin as the invasive front has been proven to be closely related to the progression and metastasis of oral squamous cell carcinoma (OSCC). However, how tumor cells in the marginal region obtain the extra energy needed for tumor progression is still unknown. Here, we used spatial metabolomics and the spatial transcriptome to identify enhanced energy metabolism in the tumor margin of OSCC and identified that the downregulation of Ras-related glycolysis inhibitor and calcium channel regulator (RRAD) in tumor cells mediated this process. The absence of RRAD enhanced the ingestion of glucose and malignant behaviors of tumor cells both in vivo and in vitro. Mechanically, the downregulation of RRAD promoted the internal flow of Ca²⁺ and elevated its concentration in the nucleus, which resulted in the activation of the CAMKIV-CREB1 axis to induce the transcription of the glucose transporter GLUT3. GLUT inhibitor-1, as an inhibitor of GLUT3, could suppress this vigorous energy metabolism and malignant behaviors caused by the downregulation of RRAD. Taken together, our study revealed that enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of OSCC and proved that GLUT3 is a potential target for future treatment of OSCC.