Abstract
ObjectivesPatients 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.MethodsProtein 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.ResultsHPV-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.ConclusionHPV-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.
Highlights
The causative role of the human papillomavirus (HPV), especially in oropharynx squamous cell carcinoma (OPSCC), is widely established [1]
Previous studies showed that the immune system is involved in the process of carcinogenesis of head and neck squamous cell carcinoma (HNSCC) and elevated levels of tumor-infiltrating lymphocytes (TILs) are associated with an improved survival [9, 25]
Summary
The causative role of the human papillomavirus (HPV), especially in oropharynx squamous cell carcinoma (OPSCC), is widely established [1]. Studies showed prevalence rates varying between 15 and 90 % of HPV-positive tumors in OPSCC worldwide and an increase is reported in the last two decades [2, 3]. Despite their general presentation at a more advanced stage, HPV-positive OPSCCs have a better survival compared to HPV-negative OPSCCs [4, 5]. Non-oropharyngeal HPV-positive head and neck squamous cell carcinoma (HNSCC) does not show this improved outcome compared to their HPV-negative counterparts [7] This observation suggests that the behavior of a HNSCC induced by HPV might be influenced by the tissue microenvironment of that specific subsite. The subepithelial tissue in the oropharynx is mainly lymphoid, indicating that especially the immune system might harbor an important clue in the different behavior of HPV-positive tumors in the oropharynx
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