Human papillomavirus (HPV) infection is one of the most important etiologic causes of oropharyngeal head and neck squamous cell carcinoma (HNSCC). Patients with HPV-positive HNSCC were reported to have a better clinical outcome than patients with HPV-negative cancers. However, little is known about the possible causes of different clinical outcomes. In this study, we analyzed a detailed immune profile of tumor samples from HNSCC patients with respect to their HPV status. We analyzed the characteristics of immune cell infiltrates, including the frequency and distribution of antigen-presenting cells and naïve, regulatory and effector T cells and the cytokine and chemokine levels in tumor tissue. There was a profound difference in the extent and characteristics of intratumoral immune cell infiltrates in HNSCC patients based on their HPV status. In contrast to HPV-negative tumor tissues, HPV-positive tumor samples showed significantly higher numbers of infiltrating IFNγ+ CD8+ T lymphocytes, IL-17+ CD8+ T lymphocytes, myeloid dendritic cells and proinflammatory chemokines. Furthermore, HPV-positive tumors had significantly lower expression of Cox-2 mRNA and higher expression of PD1 mRNA compared to HPV-negative tumors. The presence of a high level of intratumoral immune cell infiltrates might play a crucial role in the significantly better response of HPV-positive patients to standard therapy and their favorable clinical outcome. Furthermore, characterization of the HNSCC immune profile might be a valuable prognostic tool in addition to HPV status and might help identify novel targets for therapeutic strategies, including cancer immunotherapy.

• Keywords
• CD8+ T lymphocytes, Cox-2, cyclooxygenase 2, HNSCC, HNSCC, head and neck squamous cell carcinoma, HPV, HPV, human papillomavirus, PD-1, PD-1, programmed cell death 1, PD-L1, programmed cell death-ligand 1, Tim-3, Tim-3, T cell immunoglobulin and mucin protein 3, Treg, regulatory T cell, mDC, myeloid dendritic cell, pDC, plasmacytoic dendritic cell,
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Human papillomaviruses (HPVs) have been proved as one of the etiological factors of oropharyngeal squamous cell carcinoma (OPSCC). Patients with tumors of viral etiology have a lower recurrence rate and better prognosis. OPSCC is linked to an alteration in the immune system. Only a limited number of studies have correlated both the immunological parameters and HPV status with patient prognosis. The aim of this study was to determine whether HPV infection and the immunological status influence patient prognosis individually or in concurrence. MATERIAL AND METHODS: Sixty patients with oral and oropharyngeal carcinomas were enrolled. They were divided into HPV-positive and HPV-negative groups based on the expression of HPV 16 E6 mRNA. Basic lymphocyte subpopulations were determined in the peripheral blood by means of flow cytometry. RESULTS: Significantly better disease-specific survival (DSS) was observed in patients with HPV-positive tumors. Nodal status, tumor grade, recurrence, and CD8+/Tregs ratio were identified as factors influencing DSS. A higher level of Tregs and a lower ratio of CD8/Tregs influenced overall survival (OS) independently of HPV status and age. Patients with HPV-positive tumors and high levels of Tregs survived significantly better than patients from the other groups. CONCLUSION: Better survival is associated with HPV positivity and elevated Tregs levels. Our data suggest that HPV infection and Tregs do not influence patient prognosis in concurrence.

• MeSH
• Survival Analysis MeSH
• Biomarkers blood   MeSH
• Killer Cells, Natural immunology   MeSH
• Demography MeSH
• Cyclin-Dependent Kinase Inhibitor p16 metabolism   MeSH
• Middle Aged MeSH
• Humans MeSH
• Oropharyngeal Neoplasms blood   epidemiology   immunology   virology   MeSH
• Papillomaviridae physiology   MeSH
• Prognosis MeSH
• Proportional Hazards Models MeSH
• Regression Analysis MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Carcinoma, Squamous Cell blood   epidemiology   immunology   virology   MeSH
• Neoplasm Grading MeSH
• Age Factors MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Biomarkers MeSH
• Cyclin-Dependent Kinase Inhibitor p16 MeSH

The aim of the study was to investigate the role of high-risk human papillomavirus (HR-HPV) infection in the etiopathogenesis of oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinoma in non-smoking and non-drinking patients (NSNDP). Twenty-four OSCCs and 22 OPSCCs were analyzed by immunohistochemistry for p16(INK4a) protein (p16) expression and by chromogene in situ hybridization (CISH) and polymerase chain reaction (PCR) for HR-HPV DNA presence. The series included 23 males and 23 females aged 35-93 years. p16 expression was seen in 7 out of 24 (29%) OSCCs and in 22 out of 22 (100%) OPSCCs. Using CISH, HR-HPV DNA was observed in 6 out of 24 (25%) OSCCs and in 21 out of 22 (95%) OPSCCs. HPV DNA was found in 3 out of 24 (13%) OSCCs and in 18 out of 22 (82%) OPSCCs using PCR. HPV 16 and 33 were detected in 16 and in two cases, respectively. Compared with OSCCs, OPSCCs more frequently showed basaloid morphology (p < 0.0001), lymph node involvement (p = 0.0063), diffuse p16 expression (p < 0.0001), HR-HPV DNA presence using both CISH and PCR (p < 0.0001; p < 0.0001), and better outcome. The sensitivity and specificity of p16 expression for HR-HPV DNA presence detected by CISH were 0.89 and 0.95, respectively, and 0.95 and 0.85 for PCR detected HPV DNA. The sensitivity and specificity of CISH for PCR detected presence of HPV DNA were 1.00 and 0.73, respectively. Our study is the first larger study analyzing OSCC and OPSCC in NSNDP. Our results indicate that unlike OSCC, a vast majority of OPSCCs may be associated with HR-HPV infection.

• MeSH
• DNA, Viral analysis   MeSH
• Adult MeSH
• In Situ Hybridization MeSH
• Immunohistochemistry MeSH
• Papillomavirus Infections complications   MeSH
• Cyclin-Dependent Kinase Inhibitor p16 analysis   biosynthesis   MeSH
• Smoking MeSH
• Middle Aged MeSH
• Humans MeSH
• Oropharyngeal Neoplasms etiology   pathology   virology   MeSH
• Mouth Neoplasms etiology   pathology   virology   MeSH
• Alcohol Drinking MeSH
• Polymerase Chain Reaction MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sensitivity and Specificity MeSH
• Carcinoma, Squamous Cell etiology   pathology   virology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA, Viral MeSH
• Cyclin-Dependent Kinase Inhibitor p16 MeSH

High-risk types of human papillomaviruses (HR HPV) play an important role in the etiology of a group of head and neck squamous cell cancers (HNSCC). This review is focused on epidemiological, molecular, and clinical aspects of HPV infection in head and neck cancer. High risk HPV DNA is being detected in a very different proportion of HNSCC with the highest prevalence in oropharynx. Patients with HPV-associated tumors are characterized by moderate tobacco and alcohol consumption. Some aspects of sexual behavior may represent a risk factor. Recently, it has been shown that HPV infection is spreading and the rising prevalence of HPV-positive tumors can probably be attributed to this epidemic. On molecular level the viral oncoproteins E6 and E7 were shown to be involved in oncogenesis. HPV-positive cancers have better prognosis and HPV status should be considered in clinical decision-making. The rising proportion of HPV-positive tumors underlines the importance of HPV vaccination also for the prevention of HNSCC.

• MeSH
• DNA Probes, HPV MeSH
• Genome, Viral MeSH
• Papillomavirus Infections diagnosis   epidemiology   genetics   pathology   MeSH
• Humans MeSH
• Human papillomavirus 6 genetics   MeSH
• Cell Transformation, Neoplastic genetics   pathology   MeSH
• Otorhinolaryngologic Neoplasms diagnosis   epidemiology   genetics   pathology   MeSH
• Papillomavirus E7 Proteins genetics   MeSH
• Prognosis MeSH
• Cross-Sectional Studies MeSH
• Risk Factors MeSH
• Carcinoma, Squamous Cell diagnosis   epidemiology   genetics   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Names of Substances
• DNA Probes, HPV MeSH
• Papillomavirus E7 Proteins MeSH