Oropharyngeal squamous cell carcinomas differentially express granzyme inhibitors

Pauline M W van Kempen*, Rob Noorlag, Justin E. Swartz, Niels Bovenschen, Weibel W. Braunius, Jeroen F. Vermeulen, Ellen M. van Cann, Wilko Grolman, Stefan M. Willems

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review



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.


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.


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.


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.

Original languageEnglish
Pages (from-to)575-585
Number of pages11
JournalCancer Immunology, Immunotherapy
Issue number5
Publication statusPublished - 1 May 2016


  • Granzyme inhibitors
  • Human papillomavirus
  • Oropharynx squamous cell carcinoma
  • Tumor microenvironment
  • Tumor-infiltrating lymphocytes


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