Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma.
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ABSTRACT:
SUBMITTER: Sun Y
PROVIDER: S-EPMC8040311 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:HPV-related head and neck squamous cell carcinoma (HNSCC) has emerged as a diverse clinical and biological disease entity, mainly in young patients with oropharyngeal tumors who are nonsmokers and nondrinkers. Indeed, during the past few years, the pendulum has shifted towards a new epidemiological reality, the "HPV pandemic", where the majority of oropharyngeal squamous cell carcinomas (OPSCCs) are attributed to HPV. The oncogenic potential of the virus is associated to its capacity of integrating oncogenes E6 and E7 into the host cell, leading to the inactivation of several tumor suppressor genes, such as Rb. HPV status can affect prognosis in OPSCC, but its role as a predictive biomarker remains to be elucidated. Given the favorable prognosis associated with HPV-positive disease, the concept of de-escalation treatment strategies has been developed with the primary intent being the reduction of treatment-related long-term toxicities. In this review, we aim to depict current data regarding treatment de-escalation in HPV-associated OPSCC and discuss ongoing clinical trials.
| S-EPMC8473011 | biostudies-literature
Project description:Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous disease that affects more than 800,000 patients worldwide each year. The variability of HNSCC is associated with differences in the carcinogenesis processes that are caused by two major etiological agents, namely, alcohol/tobacco, and human papillomavirus (HPV). Compared to non-virally induced carcinomas, the oropharyngeal tumors associated with HPV infection show markedly better clinical outcomes and are characterized by an immunologically “hot” landscape with high levels of tumor-infiltrating lymphocytes. However, the standard of care remains the same for both HPV-positive and HPV-negative HNSCC. Surprisingly, treatment de-escalation trials have not shown any clinical benefit in patients with HPV-positive tumors to date, most likely due to insufficient patient stratification. The in-depth analysis of the immune response, which places an emphasis on tumor-infiltrating immune cells, is a widely accepted prognostic tool that might significantly improve both the stratification of HNSCC patients in de-escalation trials and the development of novel immunotherapeutic approaches.
| S-EPMC7522596 | biostudies-literature
Project description:Human papillomavirus (HPV) is an accepted cause of head and neck squamous cell carcinoma (HNSCC), and patients with HPV-associated HNSCC have a favorable prognosis. Currently, there is no general guidance on the most appropriate biomarkers for clinical assessment of HPV in these malignancies. We compared PCR-based and serologic HPV assays, as well as p16 immunohistochemistry, individually and in combination in a single population-based study to assess their associations with overall survival among patients with HNSCC, and thus their potential value as biomarkers. HPV16 serology was determined for 488 patients; immunohistochemical detection of p16 expression in tumors was conducted in a subset of 233 cases, and PCR-based methods to assess the presence of HPV16 DNA in a subset of 179 cases of tumors. Considering each biomarker individually in the subset of patients studied for all endpoints, seropositivity for the E6 and E7 proteins was significantly associated with enhanced all-cause survival in oropharyngeal disease [HR(E6/E7+) = 0.1, 95% confidence interval (CI) = 0.02-0.3]. Neither the presence of HPV16 DNA nor p16 immunostaining was associated with significant enhanced overall survival in oropharyngeal disease (HR(DNA) = 0.9, 95% CI = 0.3-2.9; HR(p16) = 0.3, 95% CI = 0.1-1.1). However, the combination of HPV-positive DNA and E6 or E7 serology was associated with enhanced overall survival in oropharyngeal disease (HR(DNA+/E6/E7+) = 0.1, 95% CI = 0.02-1.0), whereas E6/E7 seronegative patients with evidence of HPV in tumor DNA did not show any evidence of favorable survival (HR(DNA+/E6-/E7-) = 3.4, 95% CI = 0.6-18.1). Furthermore, patients with p16 staining and E6 or E7 seropositivity had favorable survival from oropharyngeal disease (HR(p16+/E6/E7+) = 0.1, 95% CI = 0.02-0.4), whereas patients who were p16 positive and E6/E7 seronegative had significantly increased hazard of all causes of death (HR(p16+/E6-/E7-) = 3.1, 95% CI = 1.2-7.7). A stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when "HPV-associated" HNSCC is defined using tumor status (HPV DNA status or P16) and HPV E6/E7 serology in combination rather using tumor HPV status alone.
| S-EPMC3463756 | biostudies-literature
Project description:HPV-associated head and neck squamous cell carcinoma (HNSCC) is a cancer entity with unique biological and clinical characteristics that requires more personalized treatment strategies. As the backbone of conventional therapeutics, radiation is now harnessed to synergize with immunotherapy in multiple malignancies. Accumulating preclinical and clinical data have suggested the potential of radioimmunotherapy in eliciting local and systemic anti-tumor response via direct killing of tumor cells and immunogenic cell death. However, this effect remains uncertain in HPV-associated HNSCC. Owing to its intrinsic radiosensitivity and distinct tumor microenvironment, HPV-associated HNSCC may represent a good candidate for radioimmunotherapy. In this review, we provide a detailed illustration of the biology, the genomic features, and immune landscapes of HPV-associated HNSCC that support the synergism between radiation and immune agents. The interaction between radiotherapy and immunotherapy is described. We also highlight the present evidence as well as ongoing trials using different combination strategies in the recurrent/metastatic or definitive settings. In addition, we have summarized the challenges and outlook for future trial design, with special emphasis on radiotherapy optimization and novel therapeutic options to incorporate.
| S-EPMC9405566 | biostudies-literature
Project description:BackgroundHead and neck squamous cell carcinoma (HNSCC) is a significant health problem and related to poor long-term outcomes, indicating more research to be done to deeply understand the underlying pathways.ObjectiveThis current study aimed in the assessment of the viral- (especially human papilloma virus [HPV]) and carcinogen-driven head and neck squamous cell carcinoma (HNSCC) microenvironment based on single-cell sequencing analysis.MethodsData were downloaded from GEO database (GSE139324), including 131224 cells from 18 HP- HNSCC patients and 8 HPV+ HNSCC patients. Following data normalization, all highly variable genes in single cells were identified, and batch correction was applied. Differentially expressed genes were identified using Wilcoxon rank sum test. A gene enrichment analysis was performed in each cell cluster using KEGG analysis. Single-cell pseudotime trajectories were constructed with MONOCLE (version 2.6.4). Cell-cell interactions were analyzed with CellChat R package. Additionally, cell-cell communication patterns in key signal pathways were compared in different tissue groups. A hidden Markov model (HMM) was used to predict gene expression states (on or off) throughout pseudotime. Five-year overall survival outcomes were compared in both HPV+ and HPV- subsets.Results20,978 high-quality individual cells passed quality control. RNA-seq data were used from 522 HNSCC primary tumor samples. 1,137 differentially expressed genes between HPV+ and HPV- HNSCC patients were investigated. 96 differentially expressed genes were associated with overall survival and highly enriched in B cell associated biological process. Cell composition differed between types of samples. MHC-I, MHC-II, and MIF signaling pathways were found to be most relevant. Within these pathways, some cells were either signal receiver or signal sender, depending on sample type, respectively. Six genes were obtained, AREG and TGFBI (upregulation), CD27, CXCR3, MS4A1, and CD19 (downregulation), whose expression and HPV types were highly associated with worse overall survival. AREG and TGFBI were pDC marker genes, CXCR3 and CD27 were significantly expressed in T cell-related cells, while MS4A1 and CD19 were mainly expressed in B naïve cells.ConclusionsThis study revealed dynamic changes in cell percentage and heterogeneity of cell subtypes of HNSCC. AREG, TGFBI, CD27, CXCR3, MS4A1, and CD19 were associated with worse overall survival in HPV-related HNSCC. Especially B-cell related pathways were revealed as particularly relevant in HPV-related HNSCC. These findings are a basis for the development of biomarkers and therapeutic targets in respective patients.
| S-EPMC9507777 | biostudies-literature
Project description:PURPOSE:We have used a genome-wide approach to identify novel differentially methylated CpG dinucleotides that are seen in different anatomic sites of head and neck squamous cell carcinoma (HNSCC), as well as those that might be related to HPV status in the oropharynx. EXPERIMENTAL DESIGN:We conducted genome-wide DNA methylation profiling of primary tumor samples and corresponding adjacent mucosa from 118 HNSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY, using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M-value). RESULTS:When datasets were individually analyzed by anatomic site of the primary tumor, we identified 293 differentially methylated CpG loci in oral cavity squamous cell carcinoma (SCC), 219 differentially methylated CpG loci in laryngeal SCC, and 460 differentially methylated in oropharyngeal SCC. A subset of these differentially methylated CpG loci was common across all anatomic sites of HNSCC. Stratification by HPV status revealed a significantly higher number of differentially methylated CpG loci in HPV+ patients. CONCLUSION:Novel epigenetic biomarkers derived from clinical HNSCC specimens can be used as molecular classifiers of this disease, revealing many new avenues of investigation for this disease.
| S-EPMC3892374 | biostudies-literature
Project description:Since there is no published randomized study comparing surgical and non-surgical therapeutic strategies in patients with oropharyngeal squamous cell carcinoma (OPSCC), the therapeutic management of these patients remains highly controversial. While human papillomavirus (HPV)-positive and HPV-negative OPSCC are now recognized as two distinct diseases with different epidemiological, biological, and clinical characteristics, the impact of HPV status on the management of OPSCC patients is still unclear. In this review, we analyze the current therapeutic options in patients with OPSCC, highlighting the most recent advances in surgical and non-surgical therapies, and we discuss the impact of HPV status on the therapeutic strategy.
| S-EPMC8582410 | biostudies-literature
Project description:IntroductionHead and neck squamous cell carcinoma (HNSCC) is among the most common cancers in the world with a low survival rate and common diagnosis at late stages. Deubiquitination of proteins is involved in tumor growth, metastasis, apoptosis, and immunosuppressive pathways. The impact of the ubiquitin-specific protease (USP4) on survival was only scarcely investigated so far. The goal of our research was to analyze the association of USP4 expression with prognosis and clinicopathological features in HNSCC.MethodsUSP4 mRNA levels were derived from The Cancer Genome Atlas (TCGA) for a cohort of 510 patients. Protein expression of USP4 was analyzed by immunohistochemistry in a second cohort of 113 patients. Associations between USP4 levels and overall survival, disease-free survival and clinicopathological data were analyzed.ResultsHigh levels of USP4 mRNA were associated with prolonged overall survival in univariable analysis. There was no more association with survival after correction for the confounders HPV, stage and smoker status. High USP4 mRNA levels were linked to a lower T-stage, the patient's age at diagnosis, and a positive HPV status. USP4 protein levels were not associated with prognosis or other features.ConclusionSince high USP4 mRNA was not an independent prognostic marker, we assume that the association is a result of the correlation of high USP4 mRNA with an HPV-positive status. Therefore, further investigation of USP4 mRNA and its association with the HPV status of HNSCC patients is warranted.
| S-EPMC10423105 | biostudies-literature
Project description:ObjectiveTo estimate the relative prognostic ability of socioeconomic status (SES) compared to overall stage for HPV-negative head and neck squamous cell carcinoma (HNSCC) MATERIALS AND METHODS: Data were obtained from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE). An empirical 4-category SES classification system was created. Cox proportional hazards models, survival gradients, Bayesian information criterion (BIC), and Harrell's C index were used to estimate the prognostic ability of SES compared to stage on overall survival (OS).ResultsThe sample consisted of 1229 patients with HPV-negative HNSCC. Patients with low SES had significantly increased risk of mortality at 5 years compared to patients with high SES (HR 3.11, 95% CI 2.07-4.67; p < 0.001), and the magnitude of effect was similar to overall stage (HR 3.01, 95% CI 2.35-3.86; p < 0.001 for stage IV versus I). Compared to overall stage, the SES classification system had a larger total survival gradient (35.8% vs. 29.1%), similar model fit (BIC statistic of 7412 and 7388, respectively), and similar model discriminatory ability (Harrell's C index of 0.61 and 0.64, respectively). The association between low SES and OS persisted after adjusting for age, sex, race, alcohol, smoking, overall stage, tumor site, and treatment in a multivariable model (HR 2.96, 95% CI 1.92-4.56; p < 0.001).ConclusionSES may have a similar prognostic ability to overall stage for patients with HPV-negative HNSCC. Future research is warranted to validate these findings and identify evidence-based interventions for addressing barriers to care for patients with HNSCC.
| S-EPMC8573717 | biostudies-literature
Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.
| S-EPMC6485194 | biostudies-literature