Identification of natural Zika virus peptides presented on the surface of paediatric brain tumour cells by HLA class I

Abstract

Despite decades of research, survival from brain cancer has scarcely improved and is drastically lower than that of other cancers. Novel therapies, such as immunotherapy, hold great promise for treating brain tumours and are desperately needed. Zika virus (ZIKV) infects and kills aggressive cancer cells with stem-like properties (CSCs) from both paediatric and adult brain tumours. Whilst T cell recruitment into ZIKV-infected brain tumours is becoming well documented, the specific mechanisms through which they are activated are poorly understood. We address this by employing a combined LC-MS/MS global proteome and immunopeptidome approach to describe, for the first time, human leukocyte antigen (HLA) presentation of ZIKV peptides on the surface of infected brain tumour cells. We first show that HLA class I (HLA-I) antigen processing & presentation is the most highly enriched immune response pathway in the global proteome of aggressive paediatric USP7-ATRT brain tumour cells following ZIKV infection. We identify USP7-ATRT cells as a good immunopeptidome model due to their homozygous of the globally most common HLA-A allotype (A*02:01). We predict the majority of the 19 ZIKV peptides that we identify here to strongly bind and be presented by HLA-A*02:01. We show that immunopeptide presentation corresponds with cellular ZIKV protein abundance, with ten peptides arising from the most abundant viral protein; non-structural protein 3 (NS3). Specifically, we show the ZIKV NS3 helicase domain to be a rich source of peptides. Finally, we verify that the identified ZIKV peptides do not mimic predicted peptides of the human proteome. The ZIKV peptides we identify here are potential candidates for developing novel epitope-specific brain tumour immunotherapies, and our findings provide potential insight into the efficacious cytotoxic T cell response that oncolytic ZIKV virotherapy can induce against brain tumours.