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| Immunology. 2022 May 21. doi: 10.1111/imm.13515 |
| NKG2A-checkpoint inhibition and its blockade critically depends on peptides presented by its ligand HLA-E. |
| Battin C1, Kaufmann G2, Leitner J3, Tobias J4, Wiedermann U5, Rölle A6, Meyer M7, Momburg F8, Steinberger P9 |
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Abstract NKG2A has emerged as a new immunotherapy target and its blockade with the novel immune checkpoint inhibitor monalizumab can boost both NK cell and CD8 T cell responses. NKG2A forms heterodimers with CD94 and binds to the human non-classical MHC class I molecule HLA-E. HLA-E forms complexes with a limited set of peptides mainly derived from the leader sequences of the classical MHC class I molecules (HLA-A, HLA-B and HLA-C) and the non-classical class I paralogue HLA-G, and it is well established that the interaction between CD94/NKG2x receptors and its ligand HLA-E is peptide-sensitive. Here, we have evaluated peptide dependence of NKG2A-mediated inhibition and the efficiency of interference by monalizumab in a transcriptional T cell reporter system. NKG2A inhibition was mediated by cell-expressed HLA-E molecules stably presenting peptides disulfate-trapped peptide ligands. We show that different HLA-class I leader peptides mediate varying levels of inhibition. We have used NKG2A/NKG2C chimeric receptors to map the binding site of NKG2A and NKG2C blocking antibodies. Furthermore, we determined the functional EC values of blocking NKG2A antibodies and show that they greatly depend on the HLA-leader peptide presented by HLA-E. Monalizumab was less effective in augmenting NK cell-mediated killing of target cells displaying HLA-G peptide on HLA-E, than cells expressing HLA-E complexed with HLA-A, HLA-B and HLA-C peptides. Our results indicate that peptides displayed by HLA-E molecules on tumor cells might influence the effectivity of NKG2A-immune checkpoint inhibitor therapy and potentially suggest novel approaches for patient stratification, e.g. based on tumoral HLA-G levels. |
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© 2022 John Wiley & Sons Ltd. |
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KEYWORDS: NKG2A, checkpoint inhibitor, monalizumab |
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Publikations ID: 35596615 Quelle: öffnen |
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