Dataset Information

Altered Toll-like receptor expression and function in HPV-associated oropharyngeal carcinoma.

ABSTRACT: Toll-like receptors (TLRs) have been widely investigated due to their importance in the inflammatory response and possible links to tumor promotion/regression and prognosis. In cancers with an infective etiology, such as human papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC), TLR responses may be activated and play a role in tumorigenesis. Our aim was to assess the expression of all TLRs in OPSCC cell lines (both HPV+ and HPV-) by qPCR, Western Blot and flow cytometry and assess their response to TLR ligands lipopolysaccharide (LPS), LPS ultra-pure (LPS-UP) and peptidoglycan (PGN) by analyzing IL-8 and IL-6 production. We also immunostained 61 OPSCC tissue samples with anti-TLR4. Results showed lower TLR1 and TLR6 mRNA expression and higher TLR9 protein expression in HPV+ when compared to HPV-OPSCC cells. TLR4 expression did not vary by HPV status in OPSCC cells, but TLR4 expression was significantly lower in HPV+OPSCC tissues. After stimulation with PGN, only one cell line (HPV+) did not secrete IL-6 or IL-8. Furthermore, HPV+OPSCC lines showed no IL-6 or IL-8 production on treatment with LPS/LPS-UP. The data suggest changes in TLR4 signaling in HPV+OPSCC, since we have shown lower tissue expression of TLR4 and no pro-inflammatory response after stimulation with LPS and LPS-UP. Also, it suggests that OPSCC may respond to HPV infection by increased expression of TLR9. This study demonstrates differences in expression and function of TLRs in OPSCC, which are dependent on HPV status, and may indicate subversion of the innate immune response by HPV infection.

SUBMITTER: Tobouti PL

PROVIDER: S-EPMC5787461 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Altered Toll-like receptor expression and function in HPV-associated oropharyngeal carcinoma.

Tobouti Priscila Lie PL Bolt Robert R Radhakrishnan Raghu R de Sousa Suzana Cantanhede Orsini Machado SCOM Hunter Keith D KD

Oncotarget 20170704 1

Toll-like receptors (TLRs) have been widely investigated due to their importance in the inflammatory response and possible links to tumor promotion/regression and prognosis. In cancers with an infective etiology, such as human papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC), TLR responses may be activated and play a role in tumorigenesis. Our aim was to assess the expression of all TLRs in OPSCC cell lines (both HPV<sup>+</sup> and HPV<sup>-</sup>) by qPCR, Western ...[more]

PMID: 29416610

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Project description:Purpose:This study aimed to compare the swallowing function in patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma treated with de-intensified chemoradiation therapy (6 weeks, 60?Gy) versus those receiving standard-of-care chemoradiation therapy (7 weeks, 70?Gy). Methods and materials:A retrospective review was conducted of 78 patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma with modified barium swallow studies pretreatment and 6 to 8 weeks posttreatment. The swallowing function was objectively scored for penetration, aspiration, and pharyngeal residue. Forty patients received de-intensified chemoradiation therapy (60?Gy image guided radiation therapy with weekly cisplatin 30?mg/m2) and 38 patients received standard-of-care chemoradiation therapy (70?Gy image guided radiation therapy with chemotherapy of the medical oncologist's choosing). Univariate and multivariate analyses were performed to detect differences between the cohorts with regard to laryngeal penetration, aspiration, and pharyngeal residue. A multivariate logistic regression was used to determine the overall effect of treatment on the swallowing function. Patient-reported swallowing outcomes in de-intensified cohort were assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Module for Head and Neck Cancer and the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events questionnaires. Results:Patients treated with de-intensified chemoradiation therapy were associated with a suggestion of lower risk of developing overall swallowing dysfunction (odds ratio [OR], 0.62; P?=?.07), laryngeal penetration (OR, 0.63; P?=?.12), and pharyngeal residue (OR, 0.61; P?=?.08). The mean pre- and 2-year post-European Organisation for Research and Treatment of Cancer Quality of Life scores pertaining to swallowing (1-4 scale, higher worse) in the de-intensified cohort were 1.4 and 1.2 for liquids; 1.2 and 1.1 for purees; 1.5 and 1.7 for solids, 1.0 and 1.3 for choked when swallowing; and 9.0 and 10.8 for composite score, respectively. The mean pre- and 2-year post-Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events swallowing difficulty scores (1-5 scale, with higher scores being worse) were 1.5 and 1.8, respectively. Conclusions:Compared with 7 weeks of 70?Gy, 6 weeks of 60?Gy de-intensified chemoradiation therapy appears to better preserve the baseline swallowing function (per objective modified barium swallow assessment). Patients treated with de-intensified chemoradiation therapy reported minimal changes in swallowing function.

Project description:The global rise of HPV(+) oropharyngeal squamous cell carcinoma (OPSCC) has generated considerable interest underlying its etiology and management. Despite an overall decline in head and neck malignancies, the incidence in OPSCC has by contrast sharply risen, with HPV(+) subtypes now comprising 80% of all OPSCC.1,2 Relative to HPV(-) OPSCC, HPV(+) patients are more responsive to chemoradiation and harbor a 52% risk-of-death reduction.3 Despite this distinct outcome, treatment regimens remain the same for all OPSCC subtypes (smoking-driven and virus-driven), rather than an adaptive approach to what most consider distinct diseases. The short-term effects (e.g., mucositis, odynophagia) and long-term toxicities (e.g., xerostomia, dysphagia, ototoxicity) from treatment substantially affect quality of life, and rival the impact of the cancer itself. Recently published as well as ongoing trials are actively examining deintensification approaches2,4-9, with the goal of diminishing treatment sequelae for HPV(+) subtypes. While deintensification may decrease chemoradiation-related toxicities, it nonetheless may also undertreat a meaningful percentage of HPV(+) patients who may then recur. In examining national trials, 19% of HPV(+) patients had disease progression after therapy, with a two-year survival rate of 60%.10 Current methods to ascertain HPV status involve p16 staining. However, on comparison with gold standard E6/E7 expression by qPCR, p16 harbored a 15% false positivity rate11, suggesting limited utility as a sole biomarker for deintensification. Improved molecular stratification would greatly enhance the clinician’s ability to precisely tailor treatment while minimizing the risk of jeopardizing outcomes. One approach encompasses in-depth proteomic profiling of HPV(+) OPSCC to reveal distinct protein expression profiles and delineate clinically relevant upstream pathways. In turn, these proteomic differences may distinguish higher-risk disease (cases predisposed to recurrence that may benefit from treatment intensification) from lower-risk phenotypes (cases whose treatment response is sufficiently robust to warrant deintensification). Here, two HPV(+) OPSCC cohorts stratified by treatment response are compared via a hybrid data dependent acquisition/data independent acquisition (DDA/DIA) approach via mass spectrometry. We focused on detection of low-abundance proteins to highlight proteomic signatures that can be potentially exploited for treatment stratification.

Project description:BACKGROUND:A subset of patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV-OSCC) experience poor clinical outcomes. The authors of this report explored prognostic risk factors for overall survival (OS) and recurrence-free survival (RFS). METHODS:Patients with incident HPV-OSCC who received treatment at the Johns Hopkins Hospital between 1997 and 2008 and who had tissue available for HPV testing as well as demographic and clinicopathologic information (N?=?176) were included. Tissue was tested for HPV by in situ hybridization (ISH) and/or p16 immunohistochemistry. Demographic and clinicopathologic information was extracted from medical records. RESULTS:In total, 157 of 176 patients (90%) with OSCC had HPV-associated disease (HPV-OSCC). In the patients with HPV-OSCC, the 3-year and 5-year OS rates were 93% (95% confidence interval [CI], 88%-98%) and 89% (95% CI, 81%-97%), respectively. Shorter survival was observed among older patients (hazard ratio [HR], 2.33 per 10-year increase; 95% CI, 1.05-5.16 per 10-year increase; P?=?.038), patients with advanced clinical T classification (HR, 5.78; 95% CI, 1.60-20.8; P?= .007), and patients who were currently using tobacco (HR, 4.38; 95% CI, 1.07-18.0; P?= .04). Disease recurrence was associated with advanced clinical T-classification (HR, 8.32; 95% CI, 3.06-23; P?<?.0001), current/former alcohol use (HR, 13; 95% CI, 1.33-120; P?= .03), and unmarried status (HR, 3.28; 95% CI, 1.20-9.00; P?= .02). Patients who remained recurrence free for 5 years had an 8.6% chance of recurrence by 10 years (1-sided 95% CI upper bound, 19%; P?= .088). CONCLUSIONS:In this study, prognostic risk factors were identified for patients with HPV-OSCC. The observed recurrence rates between 5 years and 10 years after definitive therapy need to be validated in additional studies to determine whether extended cancer surveillance is warranted in this cancer population. Cancer 2013;119:3462-3471.. © 2013 American Cancer Society.

Dataset Information

Altered Toll-like receptor expression and function in HPV-associated oropharyngeal carcinoma.

Publications

Altered Toll-like receptor expression and function in HPV-associated oropharyngeal carcinoma.

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