title: Oropharyngeal squamous cell carcinomas differentially express granzyme inhibitors.
abstract: OBJECTIVE
  Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinomas (OPSCCs) have an improved prognosis compared to HPV-negative OPSCCs. Several theories have been proposed to explain this relatively good prognosis. One hypothesis is a difference in immune response. In this study, we compared tumor-infiltrating CD3+, CD4+, CD8+ T-cells, and granzyme inhibitors (SERPINB1, SERPINB4, and SERPINB9) between HPV-positive and HPV-negative tumors and the relation with survival.
  
  
  METHODS
  Protein expression of tumor-infiltrating lymphocytes (TILs) (CD3, CD4, and CD8) and granzyme inhibitors was analyzed in 262 OPSCCs by immunohistochemistry (IHC). Most patients (67%) received primary radiotherapy with or without chemotherapy. Cox regression analysis was carried out to compare overall survival (OS) of patients with low and high TIL infiltration and expression of granzyme inhibitors.
  
  
  RESULTS
  HPV-positive OPSCCs were significantly more heavily infiltrated by TILs (p < 0.001) compared to HPV-negative OPSCCs. A high level of CD3+ TILs was correlated with a favorable outcome in the total cohort and in HPV-positive OPSCCs, while it reached no significance in HPV-negative OPSCCs. There was expression of all three granzyme inhibitors in OPSCCs. No differences in expression were found between HPV-positive and HPV-negative OPSCCs. Within the group of HPV-positive tumors, a high expression of SERPINB1 was associated with a significantly worse overall survival.
  
  
  CONCLUSIONS
  HPV-positive OPSCCs with a low count of CD3+ TILs or high expression of SERPINB1 have a worse OS, comparable with HPV-negative OPSCCs. This suggests that the immune system plays an important role in the carcinogenesis of the virally induced oropharynx tumors.
authors.affiliation: Department of Otorhinolaryngology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. p.m.w.vankempen-2@umcutrecht.nl.
authors.forename: Pauline M W
authors.initials: PM
authors.lastname: van Kempen
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Noorlag
authors.affiliation: Department of Otorhinolaryngology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Swartz
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
authors.affiliation: Department of Otorhinolaryngology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.|Department of Head and Neck Surgical Oncology, Cancer Center University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Weibel W
authors.initials: WW
authors.lastname: Braunius
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: Vermeulen
authors.affiliation: Department of Head and Neck Surgical Oncology, Cancer Center University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Van Cann
authors.affiliation: Department of Otorhinolaryngology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Wilko
authors.initials: W
authors.lastname: Grolman
authors.affiliation: Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.|Laboratory of Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Willems
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009959:Oropharyngeal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D027383:Papillomaviridae / Q000276:immunology / Q000502:physiology; D030361:Papillomavirus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D015843:Serpins / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D017252:CD3 Complex; C102316:SERPINB9 protein, human; D015843:Serpins; C051072:squamous cell carcinoma-related antigen; C075177:SERPINB1 protein, human
keywords: Granzyme inhibitors; Human papillomavirus; Oropharynx squamous cell carcinoma; Tumor microenvironment; Tumor-infiltrating lymphocytes