Abstract
The Human Leukocyte Antigen class I (HLA-I) system is an essential part of the immune system that is fundamental to the successful activation of cytotoxic lymphocytes, and an effective subsequent immune attack against both pathogen-infected and cancer cells. The importance of cytotoxic T cell activity and ability to detect foreign cancer-related antigenic peptides has recently been highlighted by the successful application of monoclonal antibody-based checkpoint inhibitors as novel immune therapies. Thus, there is an increased interest in fully characterising the repertoire of peptides that are being presented to cytotoxic CD8+ T cells by cancer cells. However, HLA-I is also known to be present on the surface of extracellular vesicles, which are released by most if not all cancer cells. Whilst the peptide ligandome presented by cell surface HLA class I molecules on cancer cells has been studied extensively, the ligandome of extracellular vesicles remains relatively poorly defined. Here, we will describe the current understanding of the HLA-I peptide ligandome and its role on cancer-derived extracellular vesicles, and evaluate the aspects of the system that have the potential to advance immune-based therapeutic approaches for the effective treatment of cancer.
Highlights
The Human Leukocyte Antigen class I (HLA-I) system is an essential part of the immune system that is fundamental to the successful activation of cytotoxic lymphocytes, and an effective subsequent immune attack against both pathogen-infected and cancer cells
Microvesicles are formed by the direct outward budding of the plasma membrane and are slightly larger Extracellular vesicles (EVs) with a size range of 150–1000 nm, whilst apoptotic bodies are formed during the process of fragmentation that occurs to cells during programmed cell death and results in the largest class of EVs at 1000–5000 nm [4]
This study provided the first set of data to confirm that EVs could effectively provide valuable information on the peptides present on HLA-I and could be assessed as essentially duplicates of the cell surface HLA-I ligandome
Summary
Extracellular vesicles (EVs) have recently become of notable interest due to their role in the mediation of intercellular communication and, in particular, their role in cancer [1]. Some of the molecules carried by cancer-derived EVs include oncoproteins and oncopeptides, as well as various RNA and DNA species that have the capacity to instigate substantial changes to the tumour microenvironment These changes often aid the progression of tumour and metastasis development as EVs have been known to feature a role in aspects of invasion and the maintenance of angiogenesis [12,13,14]. EVs have been described to release factors involved in the epithelial to mesenchymal transition process via stimulation of the epithelial cells, resulting in increased angiogenesis, extracellular matrix remodelling and the loss of adhesion of tumour cells This change in the microenvironment encourages the release of tumour cells into circulation whereby they have the ability to travel to alternative locations within the host and form metastases [14]. EVs play a number of important roles that make them excellent targets for novel immunotherapeutic techniques and for biomarker mining [18]
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