title: CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma.
abstract: Human papillomavirus (HPV)-related squamous cell carcinoma of the oropharynx (OSCC) are clinical and biological distinct from their HPV-unrelated counterparts. Patients with HPV-related OSCC display improved prognosis and therefore we investigated possible immune cell infiltrations associated with this tumor phenotype. We retrospectively analyzed a randomly selected cohort of 140 OSCC for presence of immune cells and HPV by immunohistochemistry and PCR followed by bead-based hybridization (Luminex technology). HPV prevalence was 24.3% as determined by positive staining of p16INK4a and detection of high risk HPV-DNA. We found significantly higher numbers of CD56 positive (CD56+) cells in tumor and surrounding microenvironment in HPV-associated compared to HPV-negative OSCC (t-test: p = 0.004 and p = 0.002). For the entire cohort presence of CD56+ cells was associated with increased overall survival independent from HPV (Kaplan-Meier: p = 0.002; Cox regression: p = 0.042). Presence of CD56+ cells also correlated with a better outcome in HPV-negative and especially in HPV-negative OSCC with alcohol consumption ≤ 2 standard drinks per day (Kaplan-Meier: p = 0.05 and p = 0.003). Immunofluorescence localization of granular Granzyme B (GZMB) within CD56+ cells and coexpression of CD16 and CD56 suggests that detected CD56+ cells mainly represent cytotoxic Natural Killer (NK) cells. The fraction of potentially cytotoxic NK cells was significantly higher in HPV-associated compared to HPV-negative OSCC (Mann-Whitney-U-Test: p = 0.011). The elevated abundance and activity of cytotoxic NK cells in OSCC with HPV driven carcinogenesis might contribute to favorable outcome in HPV-related OSCC.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Wittekindt
authors.affiliation: Department of Applied Tumor Biology, University of Heidelberg and Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Reuschenbach
authors.affiliation: Institute of Pathology, University of Giessen, Giessen, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Hennig
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany.
authors.forename: Mauran
authors.initials: M
authors.lastname: Thevarajah
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Würdemann
authors.affiliation: Department of Applied Tumor Biology, University of Heidelberg and Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Elena-Sophie
authors.initials: ES
authors.lastname: Prigge
authors.affiliation: Department of Applied Tumor Biology, University of Heidelberg and Clinical Cooperation Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.affiliation: Institute of Pathology, University of Giessen, Giessen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dreyer
authors.affiliation: Institute of Pathology, University of Giessen, Giessen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, Giessen, Germany.
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: Klussmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019002:CD56 Antigen / Q000096:biosynthesis / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000401:mortality / Q000821:virology*; D015331:Cohort Studies; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007694:Killer Cells, Natural / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009959:Oropharyngeal Neoplasms / Q000276:immunology* / Q000401:mortality / Q000821:virology*; D027383:Papillomaviridae; D030361:Papillomavirus Infections / Q000150:complications; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies
chemical_list: D019002:CD56 Antigen; C522918:NCAM1 protein, human
keywords: CD56; HPV; head and neck; natural killer cell; orpharyngeal squamous cell carcinoma