The HLA class I peptidome of extracellular vesicles : detection of antigenic epitopes relevant to immunotherapy

Abstract

Extracellular vesicles (EVs) have been indicated as key players in the communication between cancer cells and the host microenvironment. EVs are known to express human leukocyte antigen class I (HLA-I) molecules and the landscape of the immunopeptidome may be a defining feature of EVs that allows them to have a significant impact on anti-tumour immune responses. Whilst the peptide ligandome presented by cell surface HLA-I molecules on cancer cells has been extensively investigated, the peptide ligandome on EVs is yet to be defined. To address this, we characterised the HLA-I immunopeptidome of EVs derived from multiple myeloma and melanoma cancer cells. It was established that the HLA-I immunopeptidome on EVs can feature T cell epitopes with known immunogenicity and peptides derived from known tumour associated antigens (TAAs), as well as neoantigens. Further, due to the similarity in peptides identified between the HLA-I immunopeptidome on the cancer cell surface with that on the EVs surface, it was determined that EVs can provide insights into the effects that cancer cells may be having on the immune system. This insight could be of great clinical benefit as it suggests HLA-I on EVs can be considered a rich source of information regarding cancer, that can be obtained without an invasive biopsy. To further explore this possibility, EVs were isolated from plasma of patients diagnosed with multiple myeloma, melanoma or breast cancer and the HLA-I immunopeptidomes were characterised. Both T cell epitopes with known immunogenicity and peptides derived from known TAAs were identifiable in the patient samples. The information obtained from an easily acquired blood sample can inform on the cancer itself, may aid in the detection of important diagnostic or prognostic biomarkers, enable easier tracking of treatment responses, be utilised in novel immunotherapies and be employed as carriers for use as novel cancer vaccines.