Mining the plasma immunopeptidome for cancer peptides as biomarkers and beyond

The class I MHC-CD8+–T-cell immunosurveillance system constitutes a major component of the adaptive immune system in mammals and other jawed vertebrates. All cell types (except erythrocytes) constitutively express MHC class I molecules, which are comprised of a type I membrane-anchored glycoprotein (heavy chain) noncovalently bound to β2-microglobulin (β2m) and a peptide typically of 8–11 residues. Peptides derive from proteins synthesized by cells, often from defective ribosomal products (DRiPs), which are a subset of nascent proteins that are rapidly shunted to proteasomes for degradation because of either stochastic errors in gene expression (transcription, translation, protein folding or assembly) or a deliberate process of translating standard and nonstandard mRNAs for the purpose of immunosurveillance (1). Peptides are transported from the cytosol to the endoplasmic reticulum (ER) by an oligopeptide transporter (TAP) that also serves as a scaffold for the assembly of class I heavy chains with β2m (2). When a peptide binds with sufficient affinity, class I molecules release from TAP and are exported from the ER to the cell surface. Heavy chains are encoded by three genes (HLA-A, -B, and -C in humans) that are typically among the most polymorphic in their vertebrate species. Class I allomorphs differ in many properties, most prominently in their specificity for peptides, which is largely because of the interaction of two to three residues in the peptides with pockets in the class I binding groove. Consequently, individuals express a unique set of peptides on their cells depending on their class I genes (potentially six different allomorphs) and the peptides generated by the cells (3). In PNAS, Bassani-Sternberg et al. (4) report a nonintrusive method to mine patients’ peptide repertoires for discovering cancer biomarkers and peptide targets for immunotherapy.