Understanding HLA-E biology to advance therapeutic targeting in cancer

T-cell based immunotherapies targeting MHC-Ia-restricted peptides are often compromised by MHC-Ia down-regulation or by mutations within peptides. Although originally reported to present conserved MHC-Ia leader sequences to convey cellular health to NK cells, recent evidence from simian immunodeficiency virus /rhesus macaque CMV-driven vaccines showcase the protective role of MHC-E-restricted T cells targeting remarkably sequence- diverse peptides. Pathogen-specific HLA-E-restricted CD8+ T cells have also been identified in humans. As near monomorphic and resistant to down- regulation, MHC-E (HLA-E In humans) offers a promising “universal” target. HLA-E displays many unusual qualities that require interrogation prior to immunotherapeutic targeting. Through a highly collaborative and multi- disciplinary approach involving structural, biochemical/physical, immunopeptidomic and functional studies, we aim to (a) interrogate how atypical peptides that do not register as MHC-E binders in vitro elicit T cell responses in vivo -how do they bind MHC-E – could unknown compounds facilitate their binding (b) explore how modest binding peptides that generate unusual MHC-E conformations impact T cell recognition (b) interrogate the co- stimulatory requirements of MHC-E-restricted T cells which likely differ to MHC-Ia-restricted T cells and (d) develop new antigen discovery strategies to capture weak MHC-E binding epitope that are under-represented using current methods. The answers provided should inform therapeutic design.