Soluble HLA peptidome: A new resource for cancer biomarkers

Using circulating molecular biomarkers to screen for cancer and other debilitating disorders in a high-throughput and low-cost fashion is becoming increasingly attractive in medicine. One major limitation of investigating protein biomarkers in body fluids is that only one-fourth of the entire proteome can be routinely detected in these fluids. In contrast, Human Leukocyte Antigen (HLA) presents peptides from the entire proteome on the cell surface. While peptide-HLA complexes are predominantly membrane-bound, a fraction of HLA molecules is released into body fluids which is referred to as soluble HLAs (sHLAs). As such peptides bound by sHLA molecules represent the entire proteome of their cells/tissues of origin and more importantly, recent advances in mass spectrometry-based technologies have allowed for accurate determination of these peptides. In this perspective, we discuss the current understanding of sHLA-peptide complexes in the context of cancer, and their potential as a novel, relatively untapped repertoire for cancer biomarkers. We also review the currently available tools to detect and quantify these circulating biomarkers, and we discuss the challenges and future perspectives of implementing sHLA biomarkers in a clinical setting.