Abstract A025: Association of functionally distinct ERAP1 variants in HPV positive cancer

Human papillomavirus (HPV) infection accounts for 5% cancers worldwide, with cervical carcinoma and squamous cell carcinoma of the head and neck (SCCHN) being most common. HPV can enable immune evasion, with 50% of HPV+ SCCHN having reduced pMHC I expression, correlating with fewer tumor infiltrating lymphocytes (TIL) and a worse clinical outcome. Polymorphisms in the endoplasmic reticulum aminopeptidase1 (ERAP1), a key component of antigen processing, trimming N-terminally extended peptides for MHC I, are associated with prognosis and outcome in cervical carcinoma. We have previously demonstrated ERAP1 to be highly polymorphic, forming distinct allotypes with functional differences. Here we investigate the contribution of ERAP1 in the pathogenesis of SCCHN. We identified a number of novel ERAP1 allotype pairs (both chromosomal copies) from an HPV+ SCCHN cohort. Assessment of trimming function revealed a range of abilities to generate the model epitope SIINFEHL from individual amino acid or AIVMK precursors. Furthermore, the ability to generate HPV-16 E6/E7 specific epitopes also demonstrated varying trimming phenotypes. Interestingly, the overall ability to generate the final epitopes (model and HPV) in TIL^LOW patients was poor, whereas TIL^HIGH patients were able to generate these epitopes efficiently. This reveals ERAP1 gene sequence and function stratifies with TIL levels and prognosis, suggesting that the successful presentation of HPV-16 E6/E7 epitopes at the cell surface depends on the ERAP1 allotype pairs expressed within an individual. Furthermore, the allotype pairs correlate with levels of tumor infiltrate, suggesting ERAP1 activity as an indicator of prognosis in HPV+ SCCHN patients.

Citation Format: Emma Reeves, Emma King, Tim Elliott, Gareth Thomas, Edward James. Association of functionally distinct ERAP1 variants in HPV positive cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A025.