IUPHAR REVIEW Inhibitory checkpoints in human natural killer cells: IUPHAR Review 28 F.R. Mariotti 1 | L. Quatrini 1 | E. Munari 2 | P. Vacca 1 | N. Tumino 1 | G. Pietra 3,4 | M.C. Mingari 3,5 | L. Moretta 1 1 Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy 2 Department of Pathology, Sacro Cuore Don Calabria, Negrar, Italy 3 Laboratory of Immunology, Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino, Genoa, Italy 4 Department of Experimental Medicine (DIMES), Università di Genova, Genoa, Italy 5 Department of Experimental Medicine (DIMES), Center of Excellence for Biomedical Research, Università di Genova, Genoa, Italy Correspondence Lorenzo Moretta, Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Viale San Paolo 15, 00146 Rome, Italy. Email: lorenzo.moretta@opbg.net Funding information Fondazione Umberto Veronesi; Horizon 2020 Framework Programme, Grant/Award Number: 800924; Ministero della Salute, Grant/Award Numbers: 5x1000 2015, RF- 2016-02362288, GR-2013-02356568; Ricerca Corrente OPBG; Associazione Italiana per la Ricerca sul Cancro, Grant/Award Numbers: 5x1000 Id. 21147, IG 2017 Id.19920 Immune checkpoint inhibitors have revolutionized cancer therapy leading to excep- tional success. However, there is still the need to improve their efficacy in non- responder patients. Natural killer (NK) cells represent the first line of defence against tumours, due to their ability to release immunomodulatory cytokines and kill target cells that have undergone malignant transformation. Harnessing NK cell response will open new possibilities to improve control of tumour growth. In this respect inhibitory checkpoints expressed on these innate lymphocytes represents a promising target for next-generation immunotherapy. In this review, we will summarize recent evi- dences on the expression of NK cells receptors in cancer, with a focus on the inhibi- tory checkpoint programmed cell death protein 1 (PD-1). We will also highlight the strength and limitations of the blockade of PD-1 inhibitory pathway and suggest new combination strategies that may help to unleash more efficiently NK cell anti-tumour response. Abbreviations: AbE, abscopal effect; AML, acute myeloid leukaemia; BM, bone marrow; CAR, chimeric antigen receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DCs, dendritic cells; Gal-9, galectin-9; GvDH, graft versus host disease; HMGB-1, high-mobility group box 1; ICIs, immune checkpoint inhibitors; ITAM, immunoreceptor tyrosine-based activation motif; ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; IDO, indoleamine 2,3-dioxygenase; iPSCs, induced pluripotent stem cells; NKG2A, killer cell lection-like receptor C1; KIRs, killer immunoglobulin (Ig)-like receptors; LILRB, leukocyte Ig-like receptor subfamily B; LAG-3, lymphocyte activation gene-3; MHC-I, major histocompatibility complex class I; mAbs, monoclonal antibodies; NCRs, natural cytotoxicity receptors; NSCLC, non-small-cell lung cancer; PB, peripheral blood; PtdSer, phospatidylserine; PD-L1, programmed cell death 1 ligand 1; PD-L2, programmed cell death 1 ligand 2; PD-1, programmed cell death protein 1; RT, radiotherapy; SHP-1 and SHP-2, SH2 domain-containing phosphatase; sPD-1, soluble form of PD-1; SCCHN, squamous cell carcinomas of the head and neck; TIGIT, T-cell immunoglobulin and ITIM domain; TIM3, T-cell immunoglobulin and mucin domain-containing protein 3; TAAs, tumour-associated antigens; TILs, tumour-infiltrating lymphocytes; TMB, tumour mutational burden; UCB, umbilical cord blood. F. R. Mariotti and L. Quatrini contributed equally to this work. Received: 19 December 2019 Revised: 14 April 2020 Accepted: 15 April 2020 DOI: 10.1111/bph.15081 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society Br J Pharmacol. 2020;177:2889–2903. wileyonlinelibrary.com/journal/bph 2889