Patrolling CD8+ T cells recognize cancer cells by the snippets of cancer-specific proteins, or peptides, they present on HLA-I molecules on their surface. Cancer cells can escape such recognition when some component of the complex biochemical machinery behind this antigen presentation is compromised. These components include enzymes that cut proteins into short peptides, transporters that transfer those peptides from the cytoplasm into the endoplasmic reticulum, proteins that select the most suitable peptides for HLA binding and those that load them onto HLA molecules in preparation for their presentation. To study how deficiencies in distinct components of this machinery alter the spectrum of presented peptides on the cell surface, or “immunopeptidome”, researchers led by Ludwig Lausanne’s Michal Bassani-Sternberg and Ilja Shapiro used haploid cell lines, individually deleting eleven distinct genes encoding elements of this HLA-I peptide-presentation machinery. They reported in a March paper in Molecular & Cellular Proteomics the first collective qualitative and quantitative analysis of how the absence of individual components of that machinery affects the immunopeptidome. The absence of CALR (a folding protein), GANAB (a modifying protein) and ERAP1 (a transporter protein) induced significant, HLA allele-specific changes in peptide presentation levels. The findings should be of value to the creation of predictive tools to better prioritize the selection of antigens for personalized immunotherapies.
Deleterious knock-outs in the HLA class I antigen processing and presentation machinery induce distinct changes in the immunopeptidome
Molecular & Cellular Proteomics, 2025 March 18