HPV Epitope Processing Differences Correlate with ERAP1 Allotype and Extent of CD8⁺ T-cell Tumor Infiltration in...

Presence of tumor-infiltrating lymphocytes (TIL) predicts survival in many cancer types. In HPV-driven cancers, cervical and oropharyngeal squamous cell carcinomas (CSCC and OPSCC, respectively), numbers 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) regulates the presented peptide repertoire, trimming peptide precursors prior to MHC I loading. ERAP1 is polymorphic, and allotypic variation of ERAP1 enzyme activity has an impact on the presented peptide repertoire. Individual SNPs 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 tumor-infiltrating CD8⁺ T-cell (CD8)/TIL (CD8/TIL) status of the tumor. Functional analyses revealed that ERAP1 allotype combinations associated with CD8/TIL^low tumors have a reduced capacity to generate both a model antigen SIINFEHL and the HPV-16 E7_82-90 epitope LLMGTLGIV from N-terminally extended precursor peptides. In contrast, ERAP1 allotypes from CD8/TIL^high tumors generated the epitopes efficiently. These data reveal that ERAP1 function correlates with CD8/TIL numbers and, by implication, prognosis, suggesting that the presentation of HPV-16 epitopes at the cell surface, resulting in an anti-HPV T-cell response, may depend on the ERAP1 allotype combinations expressed within an individual.