Abstract
Human leukocyte antigen (HLA) molecules are essential for anti-tumor immunity, as they display tumor-derived peptides to drive tumor eradication by cytotoxic T lymphocytes. HLA molecules are primarily studied as peptide-loaded complexes on cell membranes (mHLA) and much less attention is given to their secretion as soluble HLA–peptide complexes (sHLA) into bodily fluids. Yet sHLA levels are altered in various pathologies including cancer, and are thus of high interest as biomarkers. Disconcordance in results across studies, however, hampers interpretation and generalization of the relationship between sHLA levels and cancer presence, thereby impairing its use as a biomarker. Furthermore, the question remains to what extent sHLA complexes exert immunomodulatory effects and whether shifts in sHLA levels contribute to disease or are only a consequence of disease. sHLA complexes can also bear tumor-derived peptides and recent advancements in mass spectrometry now permit closer sHLA peptide cargo analysis. sHLA peptide cargo may represent a “liquid biopsy” that could facilitate the use of sHLA for cancer diagnosis and target identification for therapeutic vaccination. This review aims to outline the contradictory and unexplored aspects of sHLA and to provide direction on how the full potential of sHLA as a quantitative and qualitative biomarker can be exploited.
Highlights
The field of cancer immunotherapy has undergone major advances in recent decades, facilitated by innovative strategies such as immune checkpoint inhibition, therapeutic vaccines, oncolytic viruses and adoptive T cell therapy
This study indicates that inclusion of a control group with non-malignant disease is important to determine whether elevated soluble HLA–peptide complexes (sHLA)-I levels are cancer specific or rather by-products of for example inflammatory processes
A significant fraction of the sHLA-peptidome consisted of self-peptides [120,123], cancer-specific peptides could be recovered from patient-derived sHLA-I complexes, including tumor-associated antigen (TAA)-derived peptides that may be of interest as antigenic targets for therapeutic vaccination or adoptive T cell therapy [88,91,120,123]
Summary
The field of cancer immunotherapy has undergone major advances in recent decades, facilitated by innovative strategies such as immune checkpoint inhibition, therapeutic vaccines, oncolytic viruses and adoptive T cell therapy. Human leukocyte antigen (HLA) molecules, known as major histocompatibility complex (MHC) molecules, are essential for effective immune responses. Their function is to display tumorigenic or pathogenic peptides on the cell surface membrane to flag cells for recognition and killing by cytotoxic. It is known that sHLA molecules, like mHLA molecules, carry peptides in their binding groove. These peptides, when derived from tumor-specific proteins, might provide important clues for tumor detection, but can support target identification for antigen-specific immunotherapies. For the sake of clarity, solid tumors and hematological malignancies are discussed separately
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