Differences in ERAP1 allotype function correlate with HPV epitope processing and level of tumour infiltration with CD8+ T cells in HPV-positive OPSCC

Abstract

Levels of tumour infiltrating lymphocytes (TIL) predict for survival in many cancer types. In HPV- driven cancers, cervical and oropharyngeal squamous cell carcinomas (CSCC and OPSCC respectively), levels of infiltrating T cells, particularly CD8+ T cells, and presentation of HPV E6/E7 epitopes are associated with improved prognosis. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is a key regulator of the presented peptide repertoire, trimming peptide precursors prior to MHC I loading. ERAP1 is highly polymorphic, and allotypic variation of ERAP1 enzyme activity has a significant impact on the presented peptide repertoire. Notably, individual single nucleotide polymorphisms are associated with incidence and outcome in a number of diseases, including CSCC. Here, we highlight the requirement for ERAP1 in the generation of HPV E6/E7 epitopes and show that the functional activity of ERAP1 allotype combinations identified in OPSCC correlate with CD8/TIL status of the tumour. Functional analyses revealed that ERAP1 allotype combinations associated with CD8/TILlow tumours have a significantly reduced capacity to generate both a model antigen SIINFEHL and the HPV-16 E782-90 epitope LLMGTLGIV from N-terminally extended precursor peptides. In contrast, ERAP1 allotypes from CD8/TILhigh tumours generated the epitopes efficiently. These data reveal that ERAP1 function correlates with CD8/ TIL levels and, by implication, prognosis, suggesting that the successful presentation of HPV-16 epitopes at the cell surface, and thus a strong anti-HPV T cell response, may depend on the ERAP1 allotype combinations expressed within an individual.