Strategies to disrupt NKG2A:HLA-E interactions for improved anti-cancer immunity (IMAGE)
Caption
Figure 1: Cancer therapeutics targeting the NKG2A:HLA-E axis. The NKG2A:HLA-E interaction can be inhibited by antibodies targeting either NKG2A (monalizumab, BMS-986315) or HLA-E (3H4, TFL-033). Small molecule inhibitors bortezomib and selinexor have been shown to reduce surface expression of HLA-E, sensitising tumour cells to NK cell cytotoxicity. The proteasome inhibitor bortezomib induces endoplasmic reticulum (ER) stress, potentially leading to impaired peptide loading which is crucial for expression of HLA-E at the cell surface. The precise mechanism behind the downregulation of surface HLA-E by selinexor has not yet been described. Expression of NKG2A on the surface of NK cells can also be manipulated by CRISPR-Cas9 knock-out (KO), anti-NKG2A protein expression blocker (PEBL) that can retain NKG2A in the ER, and the tyrosine kinase inhibitor dasatinib that can induce NKG2A downregulation. Overall, either blockade or downregulation of NKG2A and HLA-E relieves NK cell inhibition and improves lysis of tumour cell targets. Created with https://www.biorender.com/.
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Fisher et al.
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