Work

eHLAstic reveals an extended canonical and non-canonical HLA-E immunopeptidome in human cancers

Year: 2026

Type: article

Abstract: HLA-E is a non-classical MHC class I molecule with restricted polymorphism, offering a putative path to broadly applicable off-the-shelf therapies. Yet, the wider HLA-E peptide repertoire remains poorly defined and is largely assumed restricted to signal peptide-derived sequences. We developed eHLAstic, a dedicated HLA-E-binding predictor, that improved the precision of HLA-E ligand discovery almost 3-fold compared with existing approaches. Using eHLAstic and orthogonal biochemical validation, we report 30 previously unrecognized canonical and non-canonical HLA-E-associated peptides, including six cancer-restricted ligands detected in acute lymphoblastic and myeloid leukemia but not healthy blood or bone marrow cells. Most identified ligands were shared across individuals with diverse HLA backgrounds and were detected across hematological and solid cancers. All but one non-canonical ligands were detected exclusively in cancer-associated samples and not in healthy tissues. These findings redefine the HLA-E ligandome and uncover canonical and non-canonical HLA-E ligands with potential for immune recognition and therapeutic targeting.

Source: Cell Reports

DOI: 10.1016/j.celrep.2026.118216