ABSTRACT
Cancers often display immune escape, but the mechanisms are incompletely understood. Herein, we identify SMYD3 as a mediator of immune escape in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), an aggressive disease with poor response to immunotherapy with pembrolizumab. SMYD3 depletion induces upregulation of multiple type I interferon (IFN) response and antigen presentation machinery genes in HNSCC cells. Mechanistically, SMYD3 binds to and regulates the transcription of UHRF1, encoding for a reader of H3K9me3, which binds to H3K9me3-enriched promoters of key immune-related genes, recruits DNMT1, and silences their expression. SMYD3 further maintains the repression of immune-related genes through intragenic deposition of H4K20me3. In vivo, Smyd3 depletion induces influx of CD8+ T cells and increases sensitivity to anti-programmed death 1 (PD-1) therapy. SMYD3 overexpression is associated with decreased CD8 T cell infiltration and poor response to neoadjuvant pembrolizumab. These data support combining SMYD3 depletion strategies with checkpoint blockade to overcome anti-PD-1 resistance in HPV-negative HNSCC.
Subject(s)
Head and Neck Neoplasms , Histone-Lysine N-Methyltransferase , Interferon Type I , Papillomavirus Infections , Squamous Cell Carcinoma of Head and Neck , Humans , CCAAT-Enhancer-Binding Proteins , CD8-Positive T-Lymphocytes , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/genetics , Histone-Lysine N-Methyltransferase/genetics , Squamous Cell Carcinoma of Head and Neck/drug therapy , Squamous Cell Carcinoma of Head and Neck/genetics , Ubiquitin-Protein LigasesABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent non-skin cancer in the world. While immunotherapy has revolutionized the standard of care treatment in patients with recurrent/metastatic HNSCC, more than 70% of patients do not respond to this treatment, making the identification of novel therapeutic targets urgent. Recently, research endeavors have focused on how epigenetic modifications may affect tumor initiation and progression of HNSCC. The nuclear receptor binding SET domain (NSD) family of protein methyltransferases NSD1-NSD3 is of particular interest for HNSCC, with NSD1 and NSD3 being amongst the most commonly mutated or amplified genes respectively in HNSCC. Preclinical studies have identified both oncogenic and tumor-suppressing properties across NSD1, NSD2, and NSD3 within the context of HNSCC. The purpose of this review is to provide a better understanding of the contribution of the NSD family of protein methyltransferases to the pathogenesis of HNSCC, underscoring their promise as novel therapeutic targets in this devastating disease.
Subject(s)
Head and Neck Neoplasms , Histone-Lysine N-Methyltransferase , Humans , Squamous Cell Carcinoma of Head and Neck/genetics , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Neoplasm Recurrence, Local/genetics , Head and Neck Neoplasms/genetics , Epigenesis, GeneticABSTRACT
PURPOSE: Micronutrients and their supplementation have been investigated in the development, severity, and treatment of tinnitus. This study aimed to evaluate associations between tinnitus parameters and levels of zinc, manganese, and vitamin B12. MATERIALS AND METHODS: This retrospective study analyzed National Health and Nutrition Examination Survey 2011-2012 and 2015-2016 participants aged 20-69 who answered whether they had symptoms of tinnitus in the past year. Persons with tinnitus symptoms further reported how regularly they had symptoms and how disruptive symptoms were. Multivariable regressions accounting for age, gender, and race/ethnicity were used to evaluate the influence of low serum/blood levels of zinc, manganese, and vitamin B12 on tinnitus presence, regularity, and disruptiveness. RESULTS: This study included 9439 participants, with 16.2% of the sample reporting tinnitus symptoms. In multivariable regression models, low blood manganese was associated with tinnitus regularity (proportional OR: 1.47 [95% CI: 1.06, 2.05], p = 0.0213) and tinnitus disruptiveness (proportional OR: 1.78 [95% CI: 1.08, 2.96], p = 0.0250), but not tinnitus presence (p = 0.4813). Low serum zinc and low serum vitamin B12 did not have statistically significant associations with analyzed tinnitus parameters. CONCLUSIONS: A nationally representative analysis found that low blood manganese was significantly associated with tinnitus regularity and disruptiveness, but found that serum zinc and vitamin B12 had no association with tinnitus parameters. These findings suggest that low micronutrient levels are unlikely to be contributors to tinnitus; however, the results suggest further research on manganese supplementation in patients with tinnitus may be merited.
Subject(s)
Micronutrients , Tinnitus , Humans , Manganese , Nutrition Surveys , Retrospective Studies , Tinnitus/epidemiology , Vitamin B 12 , ZincABSTRACT
The relationship between the Naranjo scaling system and pediatric adverse drug reactions (ADR) is poorly understood. We performed a retrospective review of 1,676 pediatric ADRs documented at our hospital from 2014-2018. We evaluated patient demographics, implicated medication, ADR severity, calculated Naranjo score, associated symptoms, and location within the hospital in which the ADR was documented. ADR severity was poorly correlated with Naranjo interpretation. Out of the 10 Naranjo scale questions, 4 had a response of "unknown" greater than 85% of the time. Cardiovascular and oncological/immunologic agents were more likely to have a probable or definite Naranjo interpretation compared to antimicrobials. Further strategies are needed to enhance the causality assessment of pediatric ADRs in clinical care.
