Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive tumor with poor clinical outcomes due to recurrence, metastasis, and treatment resistance. Cancer stem cells (CSCs), a small population among tumor cells, are proposed to be responsible for tumor initiation, progression, metastasis, drug resistance, and recurrence. Here we show that high LSD1 expression was a predictor of poor prognosis for HNSCC patients. We found that high expression of LSD1 is essential for the maintenance of the CSC properties by regulating Bmi-1 expression. Moreover, tumor LSD1 ablation suppresses CSC-like characteristics in vitro and inhibits tumorigenicity in vivo in immune-deficient xenografts. However, this deletion induces the upregulation of PDL1 levels, which compromises antitumor immunity and reduces antitumor efficacy in an immune-competent mouse model. Functionally, the combination of LSD1 inhibitor and anti-PD-1 monoclonal antibody can overcome tumor immune evasion and greatly inhibit tumor growth, which was associated with reduced Ki-67 level and augmented CD8⁺ T cell infiltration in immunocompetent tumor-bearing mouse models. In summary, these findings provide a novel and promising combined strategy for the treatment of HNSCC using a combination of LSD1 inhibition and PD-1 blockade.

Background: Human papillomavirus (HPV) integration into the host genome is an important factor in HPV(+)OPSCC carcinogenesis, in conjunction with HPV oncoproteins E6/E7. However, a well‐studied investigation about virus–host interaction still needs to be completed. Our objective is to characterise HPV integration to investigate potential mechanisms of tumourigenesis independent of E6/E7 oncoproteins.Materials and methods: High‐throughput viral integration detection was performed on 109 HPV(+)OPSCC tumours with relevant clinicopathological information. Of these tumours, 38 tumours underwent targeted gene sequencing, 29 underwent whole exome sequencing and 26 underwent RNA sequencing.Results: HPV integration was detected in 94% of tumours (with a mean integration count of 337). Tumours occurring at the tonsil/oropharyngeal wall that exhibit higher PD‐L1 expression demonstrated increased integration sites (p = .024). HPV exhibited a propensity for integration at genomic sites located within specific fragile sites (FRA19A) or genes associated with functional roles such as cell proliferation and differentiation (PTEN, AR), immune evasion (CD274) and glycoprotein biosynthesis process (FUT8). The viral oncogenes E2, E4, E6 and E7 tended to remain intact. HPV fragments displayed enrichment within host copy number variation (CNV) regions. However, insertions into genes related to altered homologous recombination repair were infrequent. Genes with integration had distinct expression levels. Fifty‐nine genes whose expression level was affected by viral integration were identified, for example, EPHB1, which was reported to be involved in cellular protein metabolic process.Conclusions: HPV can promote oncogenesis through recurrent integration into functional host genome regions, leading to subsequent genomic aberrations and gene expression disruption. This study characterises viral integrations and virus–host interactions, enhancing our understanding of HPV‐related carcinogenesis mechanisms.

Dysregulated Epiregulin (EREG) can activate epidermal growth factor receptor (EGFR) and promote tumor progression in head and neck squamous cell carcinoma (HNSCC). However, the mechanisms underlying EREG dysregulation remain largely unknown. Here, we showed that dysregulated EREG was highly associated with enhanced PDL1 in HNSCC tissues. Treatment of HNSCC cells with EREG resulted in upregulated PDL1 via the c-myc pathway. Of note, we found that N-glycosylation of EREG was essential for its stability, membrane location, biological function, and upregulation of its downstream target PDL1 in HNSCC. EREG was glycosylated at N47 via STT3B glycosyltransferases, whereas mutations at N47 site abrogated N-glycosylation and destabilized EREG. Consistently, knockdown of STT3B suppressed glycosylated EREG and inhibited PDL1 in HNSCC cells. Moreover, treatment of HNSCC cells with NGI-1, an inhibitor of STT3B, blocked STT3B-mediated glycosylation of EREG, leading to its degradation and suppression of PDL1. Finally, combination of NGI-1 treatment with anti-PDLl therapy synergistically enhanced the efficacy of immunotherapy of HNSCC in vivo. Taken together, STT3B-mediated N-glycosylation is essential for stabilization of EREG, which mediates PDL1 upregulation and immune evasion in HNSCC.

Background: Salivary adenoid cystic carcinoma (SACC), a rare cancer arising in the salivary glands, is characterized by high rates of relapse and distant metastasis. Epidermal growth factor receptor (EGFR) has been implicated in SACC carcinogenesis. However, prospective trials of EGFR-targeting therapies in SACC are limited, and the optimum regimen is unclear. Methods: The effects of erlotinib on cell proliferation, colony formation, ALDH enzymatic activity and tumorsphere formation were investigated in SACC cells. Expression of the cancer stem cell markers Bmi-1 and Oct4 was evaluated using Western blotting. Results: We found that while it robustly inhibited cell growth, targeting EGFR with erlotinib enriched the ALDH⁺ cell population and elevated the clonogenicity of SACC cells, suggesting an increase in stem cell-like potential. In addition, we found that suppression of EGFR kinase activity with erlotinib led to the activation of Notch1 signaling, leading to an increase in stem cell-like properties. Moreover, the γ-secretase inhibitor GSI treatment eliminated the erlotinib-induced increase in stem cell-like properties by decreasing Notch activity. Conclusion: Our results provide an explanation for the worsened survival observed in some studies of erlotinib therapy in SACC and provide potential therapeutic strategies by combined blockade of the EGFR and Notch1 pathways.

The primary goal of peri-implantitis treatments remains the decontamination of implant surfaces exposed to polymicrobial biofilms and renders biocompatibility. In this study, we reported a synergistic strategy for the debridement and re-osteogenesis of contaminated titanium by using erythritol air abrasion (AA) coupled with an as-synthesized pH-responsive antimicrobial agent. Here, the anionic antibacterial peptide Maximin H5 C-terminally deaminated isoform (MH5C) was introduced into the Zeolitic Imidazolate Frameworks (ZIF-8) via a one-pot synthesis process. The formed MH5C@ZIF-8 nanoparticles (NPs) not only possessed suitable stability, but also guarantee the slow-release effect of MH5C. Antibacterial experiments revealed that MH5C@ZIF-8 NPs exhibited excellent antimicrobial abilities toward pathogenic bacteria of peri-implantitis, confirming ZIF-8 NPs as efficient nanoplatforms for delivering antibacterial peptide. To evaluate the comprehensive debridement efficiency, single-species as well as mixed-species biofilms were successively established on commercially used titanium surfaces and decontaminated with different methods: removed only by erythritol air abrasion, treated merely with MH5C@ZIF-8 NPs, or received both managements. The results demonstrated that only erythritol air abrasion accompanied with MH5C@ZIF-8 NPs at high concentrations eliminated almost all retained bacteria and impeded biofilm rehabilitation, while neither erythritol air abrasion nor MH5C@ZIF-8 NPs alone could achieve this. Subsequently, we evaluated the re-osteogenesis on previously contaminated surfaces which were treated with different debridement methods afterwards. We found that cell growth and osteogenic differentiation of bone marrow–derived mesenchymal stem cells (BMSCs) in the group received both treatments (AA + MH5C@ZIF-8) were higher than those in other groups. Our work emphasized the great potential of the synergistic therapy as a credible alternative for removing microorganisms and rendering re-osseointegration on contaminated implant surfaces, boding well for the comprehensive applications in peri-implantitis treatments.