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Background Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial. Methods KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019. Results Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat ( n  = 35), pembrolizumab monotherapy ( n  = 19), or EXTREME ( n  = 35). ORR (95% CI) was 31% (17%–49%) for pembrolizumab plus epacadostat, 21% (6%–46%) for pembrolizumab monotherapy, and 34% (19%–52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% ( n  = 28) of patients receiving pembrolizumab plus epacadostat, 63% ( n  = 12) receiving pembrolizumab monotherapy, and 100% ( n  = 34) receiving EXTREME. Grade 3–4 TRAEs occurred in 24% ( n  = 8) of patients receiving pembrolizumab plus epacadostat, 16% ( n  = 3) receiving pembrolizumab monotherapy, and 82% ( n  = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects. Conclusions Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC. Trial registration NCT03358472. Date of trial registration: November 30, 2017.

The treatment of locoregional recurrence (LRR) of head and neck squamous cell carcinoma (HNSCC) often requires a combination of surgery, radiation therapy and/or chemotherapy. Survival outcomes are poor and the treatment outcomes are morbid. Cold atmospheric plasma (CAP) is an ionized gas produced at room temperature under laboratory conditions. We have previously demonstrated that treatment with a CAP jet device selectively targets cancer cells using in vitro melanoma and in vivo bladder cancer models. In the present study, we wished to examine CAP selectivity in HNSCC in vitro models, and to explore its potential for use as a minimally invasive surgical approach that allows for specific cancer cell or tumor tissue ablation without affecting the surrounding healthy cells and tissues. Four HNSCC cell lines (JHU-022, JHU-028, JHU-029, SCC25) and 2 normal oral cavity epithelial cell lines (OKF6 and NOKsi) were subjected to cold plasma treatment for durations of 10, 30 and 45 sec, and a helium flow of 20 l/min−1 for 10 sec was used as a positive treatment control. We showed that cold plasma selectively diminished HNSCC cell viability in a dose-response manner, as evidenced by MTT assays; the viability of the OKF6 cells was not affected by the cold plasma. The results of colony formation assays also revealed a cell-specific response to cold plasma application. Western blot analysis did not provide evidence that the cleavage of PARP occurred following cold plasma treatment. In conclusion, our results suggest that cold plasma application selectively impairs HNSCC cell lines through non-apoptotic mechanisms, while having a minimal effect on normal oral cavity epithelial cell lines.

Background Head and neck squamous cell carcinoma (HNSCC) treatment faces significant clinical challenges. Lactate metabolism plays a crucial role in the initiation of many cancers and the tumor microenvironment (TME). However, the prognostic significance of lactate metabolism-related genes (LMRGs) and the role of TME in HNSCC require further elucidation. Methods We built a prognostic multigene signature with LMRGs and systematically correlated the risk signature with immunological characteristics and immunotherapy efficacy. Next, a series of single-cell sequencing analyses were used to characterize lactate metabolism in TME. Finally, single-cell sequencing analysis, immunofluorescence analyses, and a series of in vitro experiments were used to explore the role of PYGL in HNSCC. Potential drugs targeting PYGL were screened using AutoDock 4.2. Results A prognostic multigene signature based on LMRGs was developed, which effectively stratified patients into high- and low-risk groups, with significant differences in overall survival (OS) and progression-free survival (PFS). Patients in the low-risk group exhibited reduced lactate metabolism, higher CD8 + T cell infiltration, and improved response to immunotherapy. Single-cell sequencing revealed that tumor cells had the most active lactate metabolism compared to other cells in the TME. PYGL, identified as the most critical prognostic gene, was highly expressed in tumor-associated macrophages and played a role in inhibiting M1 macrophage polarization. Knockdown of PYGL led to reduced lactate levels, and its expression was inversely correlated with CD8 + T cell infiltration. Furthermore, PYGL was involved in copper-dependent cell death, highlighting its potential as a therapeutic target. Drug screening identified elesclomol, which showed promising results in PYGL-knockdown cells. Conclusions The study established a robust LMRGs-based prognostic model that not only predicts patient survival but also correlates with the immune microenvironment in HNSCC. PYGL emerged as a key biomarker with significant implications for both prognosis and therapeutic intervention. Its role in regulating lactate metabolism and immune suppression suggests that targeting PYGL could enhance the efficacy of immunotherapies. This research provides a foundation for future clinical strategies aimed at improving outcomes in HNSCC by modulating the tumor’s metabolic and immune landscapes.

BackgroundPreviously reported results from phase III KEYNOTE-048 demonstrated similar or improved overall survival (OS) with pembrolizumab or pembrolizumab-chemotherapy versus cetuximab-chemotherapy (EXTREME) in Japanese patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). We report results in Japanese patients from KEYNOTE-048 after 5 years of follow-up.MethodsPatients with R/M HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Primary endpoints were OS and progression-free survival. Efficacy was evaluated in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, PD-L1 CPS ≥ 1, and total Japanese populations.ResultsIn Japan, 67 patients were enrolled (pembrolizumab, n = 23; pembrolizumab-chemotherapy, n = 25; EXTREME, n = 19). Median follow-up was 71.0 months (range, 61.2–81.5); data cutoff, February 21, 2022. 5-year OS rates with pembrolizumab versus EXTREME were 35.7% versus 12.5% (hazard ratio [HR] 0.38; 95% CI 0.13–1.05), 23.8% versus 12.5% (HR 0.70; 95% CI 0.34–1.45), and 30.4% versus 10.5% (HR 0.54; 95% CI 0.27–1.07) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. 5-year OS rates with pembrolizumab-chemotherapy versus EXTREME were 20.0% versus 14.3% (HR 0.79; 95% CI 0.27–2.33), 10.5% versus 14.3% (HR 1.18; 95% CI 0.56–2.48), and 8.0% versus 12.5% (HR 1.11; 95% CI 0.57–2.16) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively.ConclusionAfter 5 years of follow-up, pembrolizumab and pembrolizumab-chemotherapy showed long-term clinical benefits; results further support these treatments as first-line options for Japanese patients with R/M HNSCC.Clinical trial registrationNCT02358031.

Background Heat shock 90 kDa protein ATPase homolog 1 (AHSA1), a chaperone of heat shock protein 90 (Hsp90), is upregulated in various malignancies, where it promotes the invasion, migration, and proliferation of cancer cells. Nevertheless, the precise function of AHSA1 in head and neck squamous cell carcinoma (HNSCC) has yet to be investigated. Methods To comprehensively investigate AHSA1 profiles of expression in HNSCC, various techniques including bioinformatics analysis of public databases and qRT-PCR were utilized. To evaluate AHSA1’s clinical significance in HNSCC, survival analysis was performed using Cox regression models and Kaplan-Meier curves. The associations between AHSA1 expression, immune microenvironment characteristics, and drug sensitivity were analyzed through bioinformatics approaches. The cellular localization and potential functions of AHSA1 in HNSCC were further investigated through single-cell RNA sequencing (scRNA-seq) analysis. Ultimately, both in vitro and in vivo experimental techniques were used to examine the biological functions of AHSA1 in HNSCC tumor growth and metastasis. Results In HNSCC, AHSA1 expression was markedly upregulated and showed strong associations with clinicopathological factors such as disease stage, TP53 mutation status, and HPV infection status. Survival analysis identified AHSA1 as an independent prognostic biomarker, with elevated expression correlating with adverse clinical outcomes. Notably, an inverse relationship was observed between AHSA1 levels and tumor-infiltrating immune cell populations. Drug sensitivity analysis revealed enhanced therapeutic responsiveness to multiple chemotherapeutic agents in tumors with high AHSA1 expression. Functional validation experiments demonstrated that AHSA1 silencing suppressed tumor growth in HNSCC mice and significantly suppressed cellular proliferation, migration, and invasive potential. Conclusion In HNSCC patients, AHSA1 might be a useful biomarker for prognostic evaluation and guidance for immunotherapy. Furthermore, inhibition of AHSA1 could effectively suppress tumor growth, invasion, and migration, underscoring its potential for HNSCC treatment strategies.

Partial epithelial‐to‐mesenchymal transition (pEMT) contributes to cellular heterogeneity that is associated with nodal metastases and unfavorable clinical parameters in head and neck squamous cell carcinomas (HNSCCs). We developed a single‐cell RNA sequencing signature‐based pEMT quantification through cell type‐dependent deconvolution of bulk RNA sequencing and microarray data combined with single‐sample scoring of molecular phenotypes (Singscoring). Clinical pEMT‐Singscores served as molecular classifiers in multivariable Cox proportional hazard models and high scores prognosticated poor overall survival and reduced response to irradiation as independent parameters in large HNSCC cohorts [The Cancer Genome Atlas (TCGA), MD Anderson Cancer Centre (MDACC), Fred Hutchinson Cancer Research Center (FHCRC)]. Differentially expressed genes confirmed enhanced cell motility and reduced oxidative phosphorylation and epithelial differentiation in pEMThigh patients. In patients and cell lines, the EMT transcription factor SLUG correlated most strongly with pEMT‐Singscores and promoted pEMT, enhanced invasion, and resistance to irradiation in vitro. SLUG protein levels in HNSCC predicted disease‐free survival, and its peripheral expression at the interphase to the tumor microenvironment was significantly increased in relapsing patients. Hence, pEMT‐Singscores represent a novel risk predictor for HNSCC stratification regarding clinical outcome and therapy response that is partly controlled by SLUG. In a combinatorial approach, a single‐cell RNA sequencing‐derived partial epithelial‐to‐mesenchymal transition (pEMT) gene signature was transferred to bulk sequencing data from large head and neck squamous cell carcinoma cohorts using single‐sample scoring (Singscoring). Patient‐specific pEMT‐SingScores prognosticated patient overall survival and reduced response to irradiation as an independent parameter. pEMT‐SingScores correlated with the expression of the transcription factor Slug, which induced characteristics of pEMT and correlated with reduced disease‐free survival.

BackgroundSERPINE1 has attracted considerable attention in tumor biology, but its clinical importance in head and neck squamous cell carcinoma (HNSCC) is not yet clear. We therefore examined whether SERPINE1 expression is related to survival in patients with HNSCC.MethodsWe searched three major databases (PubMed, EMBASE, and the Cochrane Library) and identified observational studies reporting survival outcomes in relation to SERPINE1 expression through November 11, 2024. From eligible reports we extracted data on progression-free survival (PFS), overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS), and calculated pooled hazard ratios (HRs) using random-effects models.ResultsEleven studies including 733 individuals with HNSCC met the inclusion criteria. Across these cohorts, higher SERPINE1 expression was consistently linked with shorter OS (HR 2.81,  = 0.003) and shorter DFS (HR 1.57,  = 0.004). In contrast, no clear associations were observed for PFS or DSS (  ≥ 0.05).ConclusionCurrent evidence suggests that increased SERPINE1 expression is associated with an unfavorable prognosis in HNSCC, particularly for OS and DFS. Larger prospective studies are needed to confirm these findings and to determine how SERPINE1 assessment might be incorporated into risk stratification and treatment planning for patients with HNSCC.

Background Histone H2B is highly expressed in many types of cancers and is involved in cancer development. H2B clustered histone 9 ( H2BC9 ), a member of the H2B family, plays critical roles in gene expression regulation, chromosome structure, DNA repair stability, and cell cycle regulation. However, the diagnostic and prognostic value of H2BC9 in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study aimed to evaluate the potential diagnostic and prognostic value of H2BC9 in HNSCC and investigate its biological role using bioinformatics. Methods The expression pattern and diagnostic value of H2BC9 in HNSCC were explored using UCSC Xena and GEO database. H2BC9 expression was validated using the Human Protein Atlas database, qRT-PCR, and western blotting. Prognostic value was assessed using Kaplan–Meier curves, Cox regression analysis, and a nomogram. Drug sensitivity was predicted using the R package pRRophetic, and molecular interactions were analyzed using the DepMap database. The impact of H2BC9 on HNSCC cells was further investigated through in vitro experiments. Results H2BC9 was markedly upregulated in HNSCC cell lines and tissues. High expression of H2BC9 was correlated with advanced-stage disease and poor prognosis. KEGG analysis linked H2BC9 to cell cycle regulation and DNA replication. H2BC9 expression influenced the drug sensitivity of paclitaxel, docetaxel, cisplatin, and 5-fluorouracil. Key molecules, such as TONSL , PITX2 , NOTCH1 , and H2BC10 , were positively correlated with H2BC9 expression. Silencing H2BC9 suppressed cell proliferation, induced G2/M cell cycle arrest, and enhanced apoptosis and DNA damage in HNSCC cells. Conclusion We demonstrated that H2BC9 expression may be associated with HNSCC development and prognosis. These findings may provide a potential therapeutic target for HNSCC.

Patients with head and neck squamous cell carcinoma (HNSCC) are at a high risk of developing recurrence and secondary cancers. This study evaluates the prognostic and surveillance utilities of circulating tumour cells (CTCs) in HNSCC. A total of 154 HNSCC patients were recruited and followed up for 4.5 years. Blood samples were collected at baseline and follow-up. CTCs were isolated using a spiral microfluid device. Recurrence and death due to cancer were assessed during the follow-up period. In patients with HNSCC, the presence of CTCs at baseline was a predictor of recurrence (OR = 8.40, p  < 0.0001) and death (OR= ∞, p  < 0.0001). Patients with CTCs at baseline had poor survival outcomes ( p  < 0.0001). Additionally, our study found that patients with CTCs in a follow-up appointment were 2.5 times more likely to experience recurrence or death from HNSCC ( p  < 0.05) prior to their next clinical visit. Our study highlights the prognostic and monitoring utilities of CTCs’ in HNSCC patients. Early identification of CTCs facilitates precise risk assessment, guiding treatment choices and ultimately enhancing patient outcomes.

In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors (cetuximab) and immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) have come to be used. The importance of anti-cancer drug therapy is increasing year by year. Therefore, we summarize clinical trials of molecular targeted therapy and biomarkers in HNSCC from previous studies. Here we show the current trends and future prospects of molecular targeted therapy in HNSCC.