cancers Review Natural Killer Cells and Anti-Cancer Therapies: Reciprocal Effects on Immune Function and Therapeutic Response Elisa C. Toffoli 1,†, Abdolkarim Sheikhi 1,2,†, Yannick D. Höppner 1 , Pita de Kok 1, Mahsa Yazdanpanah-Samani 3 , Jan Spanholtz 4, Henk M. W. Verheul 5 , Hans J. van der Vliet 1,6 and Tanja D. de Gruijl 1,* 1 Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; [email protected] (E.C.T.); [email protected] (A.S.); [email protected] (Y.D.H.); [email protected] (P.d.K.); [email protected] (H.J.v.d.V.) 2 Department of Immunology, School of Medicine, Dezful University of Medical Sciences, Dezful 64616-43993, Iran 3 Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz 71348-45794, Iran; [email protected] 4 Glycostem, Kloosterstraat 9, 5349 AB Oss, The Netherlands; [email protected] 5 Department of Medical Oncology, Radboud Institute for Health Sciences, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands; [email protected] 6 Lava Therapeutics, Yalelaan 60, 3584 CM Utrecht, The Netherlands * Correspondence: [email protected]; Tel.: +31-20-4444063 † These authors contributed equally to this paper. Citation: Toffoli, E.C.; Sheikhi, A.; Simple Summary: Natural Killer (NK) cells are innate lymphocytes that play an important role Höppner, Y.D.; de Kok, P.; in the immune response against cancer. Their activity is controlled by a balance of inhibitory and Yazdanpanah-Samani, M.; activating receptors, which in cancer can be skewed to favor their suppression in support of immune Spanholtz, J.; Verheul, H.M.W.; escape. It is therefore imperative to find ways to optimize their antitumor functionality. In this van der Vliet, H.J.; de Gruijl, T.D. review, we explore and discuss how their activity influences, or even mediates, the efficacy of various Natural Killer Cells and Anti-Cancer anti-cancer therapies and, vice versa, how their activity can be affected by these therapies. Knowledge Therapies: Reciprocal Effects on Immune Function and Therapeutic of the mechanisms underlying these observations could provide rationales for combining anti-cancer Response. Cancers 2021, 13, 711. treatments with strategies enhancing NK cell function in order to improve their therapeutic efficacy. https://doi.org/10.3390/cancers 13040711 Abstract: Natural Killer (NK) cells are innate immune cells with the unique ability to recognize and kill virus-infected and cancer cells without prior immune sensitization. Due to their expression of the Academic Editor: Michael Kershaw Fc receptor CD16, effector NK cells can kill tumor cells through antibody-dependent cytotoxicity, Received: 31 December 2020 making them relevant players in antibody-based cancer therapies. The role of NK cells in other Accepted: 6 February 2021 approved and experimental anti-cancer therapies is more elusive. Here, we review the possible role Published: 9 February 2021 of NK cells in the efficacy of various anti-tumor therapies, including radiotherapy, chemotherapy, and immunotherapy, as well as the impact of these therapies on NK cell function. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: NK cells; radiotherapy; local ablation therapies; checkpoint inhibitors; chemotherapy; published maps and institutional affil- protein kinase inhibitors; oncolytic virus; cancer; anti-cancer therapies iations. 1. Introduction Copyright: © 2021 by the authors. Natural killer (NK) cells are large granular lymphocytes, part of the innate immune Licensee MDPI, Basel, Switzerland. system, and are characterized by the expression of CD56, the absence of CD3 [1], and This article is an open access article the ability to kill virus-infected and tumor cells without prior immune sensitization [2]. distributed under the terms and conditions of the Creative Commons Classically, NK cells can be divided into two main subsets with distinct properties: the dim bright Attribution (CC BY) license (https:// CD56 effector NK cells with high cytotoxic capacity and the CD56 NK cells, which creativecommons.org/licenses/by/ exert mainly a regulatory function [3]. NK cell activity is controlled by a balance of 4.0/). inhibitory and activating receptors (Figure1)[ 1]. Killer cell immunoglobulin-like receptors Cancers 2021, 13, 711. https://doi.org/10.3390/cancers13040711 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x FOR PEER REVIEW 2 of 28 Cancers 2021, 13, 711 2 of 27 inhibitory and activating receptors (Figure 1) [1]. Killer cell immunoglobulin-like (KIR)receptors and the(KIR) natural and the killer natural receptor killer (NKG) recept 2Aor are (NKG) examples 2A are of inhibitoryexamples receptorsof inhibitory that are importantreceptors that to suppress are important non-specific to suppress cytotoxic non-specific activity and cytotoxic killing ofactivity healthy and cells. killing They of bind tohealthy multiple cells. human They leukocytebind to multiple antigens human (HLA), leukocyte which can antigens be downregulated (HLA), which by tumorcan be and virus-infecteddownregulated cells by tumor to escape and T virus-infected cell recognition cells leading to escape to increased T cell recognition NK cell recognition. leading to In addition,increasedNK NK cellscell recognition. can express In other addition, inhibitory NK cells receptors can express recognizing other inhibitory non-MHC receptors molecules, suchrecognizing as the Lectin-likenon-MHC molecules, Transcript-1 such (LLT-1), as thewhich Lectin-like binds Transcript-1 to NKR-P1A. (LLT-1), The activatingwhich receptors,binds to NKR-P1A. such as natural The activating killer group receptors, 2 member such (NKG2)D/C/E, as natural killer and group natural 2 member cytotoxicity receptors(NKG2)D/C/E, (NCRs), and suchnatural as NKp30,cytotoxicity NKp46, receptors and (NCRs), NKp44, such recognize as NKp30, specific NKp46, ligands, and like MHCNKp44, class recognize I polypeptide–related specific ligands, like sequence MHC A/Bclass I (MICA/B), polypeptide–related UL16 binding sequence protein A/B 1-6 (ULBP1-6),(MICA/B), andUL16 heparan binding sulfate protein proteoglycan 1-6 (ULBP1-6), (HSPG), and thatheparan are overexpressed sulfate proteoglycan by infected and(HSPG), malignant that are cells overexpressed [1,2]. When by the infected balance an ofd thesemalignant receptors cells is[1,2]. skewed When towards the balance activation, of these receptors is skewed towards activation, either due to a lack of inhibitory signals or either due to a lack of inhibitory signals or the dominance of activating signals, NK cells the dominance of activating signals, NK cells are triggered to release cytotoxic granules are triggered to release cytotoxic granules and cytotoxic effector proteins like granzymes and cytotoxic effector proteins like granzymes and perforin in order to kill the target cell and perforin in order to kill the target cell [4,5]. NK cells can also induce apoptosis via [4,5]. NK cells can also induce apoptosis via Fas ligand and tumor necrosis factor (TNF)– Fas ligand and tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL), related apoptosis-inducing ligand (TRAIL), which bind to the Fas receptor and the death which bind to the Fas receptor and the death receptor 5 (DR5) expressed on target cells [4]. receptor 5 (DR5) expressed on target cells [4]. Moreover, thanks to the expression of CD16 Moreover, thanks to the expression of CD16 (Fc receptor: FcRγIII), NK cells can also kill (Fc receptor: FcRγIII), NK cells can also kill through antibody-dependent cell-mediated throughcytotoxicity antibody-dependent (ADCC) [6]. cell-mediated cytotoxicity (ADCC) [6]. FigureFigure 1.1. Overview of of major major natural natural killer killer (NK) (NK) cell cell activating activating and andinhibitory inhibitory receptors receptors and their and their corresponding ligands expressed on tumor cells. KIR: killer cell immunoglobulin-like receptors; corresponding ligands expressed on tumor cells. KIR: killer cell immunoglobulin-like receptors; NKG: NKG: natural killer receptor; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; natural killer receptor; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; NCR: natural cytotoxicity receptors; HLA: human leukocyte antigen; MICA: MHC class I polypeptide–related sequence; PVR: poliovirus receptor; DR5: death receptor 5; DNAM1: DNAX Accessory Molecule-1, ULBP1-6: UL16 binding protein 1-6, LLT-1: lectin-like Transcript-1. Cancers 2021, 13, x FOR PEER REVIEW 3 of 28 Cancers 2021, 13, 711 3 of 27 NCR: natural cytotoxicity receptors; HLA: human leukocyte antigen; MICA: MHC class I polypeptide–related sequence; PVR: poliovirus receptor; DR5: death receptor 5; DNAM1: DNAX Accessory Molecule-1, ULBP1-6: UL16 binding protein 1-6, LLT-1: lectin-like Transcript-1. 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