NKG2A‐checkpoint inhibition and its blockade critically depends on peptides presented by its ligand HLA‐E

• DOI: 10.1111/imm.13515
• Publication Date: 2022-05-21T08:08:36Z
• Authors: Claire Battin; Gabriel Kaufmann; Judith Leitner; Joshua Tobias; Ursula Wiedermann; Alexander Rölle; Marten Meyer; Frank Momburg; Peter Steinberger
• Keywords: Immune checkpoint

NKG2A has emerged as a new immunotherapy target and its blockade with the novel immune checkpoint inhibitor (ICI) monalizumab can boost both NK cell CD8+ T responses. forms heterodimers CD94 binds to human non-classical MHC class I molecule HLA-E. HLA-E complexes limited set of peptides mainly derived from leader sequences classical molecules (HLA-A, HLA-B HLA-C) paralogue HLA-G, it is well established that interaction between CD94/NKG2x receptors ligand peptide-sensitive. Here, we have evaluated peptide dependence NKG2A-mediated inhibition efficiency interference by in transcriptional reporter system. was mediated cell-expressed stably presenting disulfate-trapped ligands. We show different HLA-class mediate varying levels inhibition. used NKG2A/NKG2C chimeric map binding site NKG2C blocking antibodies. Furthermore, determined functional EC50 values antibodies they greatly depend on HLA-leader presented Monalizumab less effective augmenting cell-mediated killing cells displaying HLA-G HLA-E, than expressing complexed HLA-A, HLA-C peptides. Our results indicate displayed tumour might influence effectivity NKG2A-ICI therapy potentially suggest approaches for patient stratification, example, based tumoral levels.