Immunotherapeutic targeting of activating natural killer cell receptors and their ligands in cancer

• Published in: Clinical and experimental immunology 2022-07, Vol.209 (1), p.22-32
• Main Authors: Peipp, Matthias, Klausz, Katja, Boje, Ammelie Svea, Zeller, Tobias, Zielonka, Stefan, Kellner, Christian
• Format: Article
• Language: English
• Subjects: Humans; Immunotherapy; Killer Cells, Natural; Ligands; Neoplasms; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Receptors, Natural Killer Cell; Review Series: Immune cell-antibody interactions in health and disease (Series Editors: Sophia Karagiannis and James Arnold)
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1093/cei/uxac028

Natural killer (NK) cells exert an important role in cancer immune surveillance. Recognition of malignant cells and controlled activation of effector functions are facilitated by the expression of activating and inhibitory receptors, which is a complex interplay that allows NK cells to discriminate malignant cells from healthy tissues. Due to their unique profile of effector functions, the recruitment of NK cells is attractive in cancer treatment and a key function of NK cells in antibody therapy is widely appreciated. In recent years, besides the low-affinity fragment crystallizable receptor for immunoglobulin G (FcγRIIIA), the activating natural killer receptors p30 (NKp30) and p46 (NKp46), as well as natural killer group 2 member D (NKG2D), have gained increasing attention as potential targets for bispecific antibody-derivatives to redirect NK cell cytotoxicity against tumors. Beyond modulation of the receptor activity on NK cells, therapeutic targeting of the respective ligands represents an attractive approach. Here, novel therapeutic approaches to unleash NK cells by engagement of activating NK-cell receptors and alternative strategies targeting their tumor-expressed ligands in cancer therapy are summarized.