Inhibitory receptors for HLA class I as immune checkpoints for natural killer cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy

Nicky A Beelen, Femke A I Ehlers, Gerard M J Bos, Lotte Wieten*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review


Natural killer (NK) cells mediate potent anti-tumor responses, which makes them attractive targets for immunotherapy. The anti-tumor response of endogenous- or allogeneic NK cells can be enhanced through clinically available monoclonal antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC). NK cell activation is regulated by interaction of inhibitory receptors with classical- and non-classical human leukocyte antigens (HLA) class I molecules. Inhibitory receptors of the killer immunoglobulin-like receptor (KIR) family interact with HLA-A, -B or -C epitopes, while NKG2A interacts with the non-classical HLA-E molecule. Both types of inhibitory interactions may influence the strength of the ADCC response. In the present review, we provide an overview of the effect of inhibitory KIRs and NKG2A on NK cell-mediated ADCC, which highlights the rationale for combination strategies with ADCC triggering antibodies and interference with the NK cell relevant inhibitory immune checkpoints, such as KIR and NKG2A.

Original languageEnglish
Pages (from-to)797-804
Number of pages8
JournalCancer Immunology Immunotherapy
Issue number4
Early online date19 Oct 2022
Publication statusPublished - Apr 2023

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