. 2020 Dec; 54(1):44-58.

Harnessing NK cells for cancer immunotherapy: immune checkpoint receptors and chimeric antigen receptors

Nayoung Kim 1 Dong-Hee Lee 1 Woo Seon Choi 2 Eunbi Yi 2 HyoJeong Kim 2 Jung Min Kim 3 Hyung-Seung Jin 1 Hun Sik Kim 4 
  • PMID: 33298244
  •     141 References
  •     3 citations


Natural killer (NK) cells, key antitumor effectors of the innate immune system, are endowed with the unique ability to spontaneously eliminate cells undergoing a neoplastic transformation. Given their broad reactivity against diverse types of cancer and close association with cancer prognosis, NK cells have gained considerable attention as a promising therapeutic target for cancer immunotherapy. NK cell-based therapies have demonstrated favorable clinical efficacies in several hematological malignancies but limited success in solid tumors, thus highlighting the need to develop new therapeutic strategies to restore and optimize anti-tumor activity while preventing tumor immune escape. The current therapeutic modalities yielding encouraging results in clinical trials include the blockade of immune checkpoint receptors to overcome the immune-evasion mechanism used by tumors and the incorporation of tumor-directed chimeric antigen receptors to enhance NK cell anti-tumor specificity and activity. These observations, together with recent advances in the understanding of NK cell activation within the tumor microenvironment, will facilitate the optimal design of NK cell-based therapy against a broad range of cancers and, more desirably, refractory cancers. [BMB Reports 2021; 54(1): 44-58].

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Ana C Anderson, Nicole Joller, Vijay K Kuchroo.
Immunity, 2016 May 19; 44(5). PMID: 27192565    Free PMC article.
Highly Cited. Review.
Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells.
Lenka V Hurton, Harjeet Singh, +12 authors, Laurence J N Cooper.
Proc Natl Acad Sci U S A, 2016 Nov 17; 113(48). PMID: 27849617    Free PMC article.
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Evaluation of the Anti-Tumor Activity of the Humanized Monoclonal Antibody NEO-201 in Preclinical Models of Ovarian Cancer.
Kristen P Zeligs, Maria Pia Morelli, +14 authors, Christina M Annunziata.
Front Oncol, 2020 Jul 09; 10. PMID: 32637350    Free PMC article.
HLA-E expression by gynecological cancers restrains tumor-infiltrating CD8⁺ T lymphocytes.
Marloes Gooden, Margit Lampen, +5 authors, Thorbald van Hall.
Proc Natl Acad Sci U S A, 2011 Jun 15; 108(26). PMID: 21670276    Free PMC article.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
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A synergistic interferon-gamma production is induced by mouse hepatitis virus in interleukin-12 (IL-12)/IL-18-activated natural killer cells and modulated by carcinoembryonic antigen-related cell adhesion molecules (CEACAM) 1a receptor.
Alexandre Jacques, Christian Bleau, +2 authors, Lucie Lamontagne.
Immunology, 2009 Sep 25; 128(1 Suppl). PMID: 19740316    Free PMC article.
NKG2A Blockade Potentiates CD8 T Cell Immunity Induced by Cancer Vaccines.
Nadine van Montfoort, Linda Borst, +13 authors, Thorbald van Hall.
Cell, 2018 Dec 07; 175(7). PMID: 30503208    Free PMC article.
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Engineering Natural Killer Cells for Cancer Immunotherapy.
Katayoun Rezvani, Rayne Rouce, Enli Liu, Elizabeth Shpall.
Mol Ther, 2017 Jul 03; 25(8). PMID: 28668320    Free PMC article.
Highly Cited. Review.
CTLA-4⁺ Regulatory T Cells Increased in Cetuximab-Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis.
Hyun-Bae Jie, Patrick J Schuler, +5 authors, Robert L Ferris.
Cancer Res, 2015 Apr 03; 75(11). PMID: 25832655    Free PMC article.
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Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization.
Silvia Pesce, Marco Greppi, +6 authors, Emanuela Marcenaro.
J Allergy Clin Immunol, 2016 Jul 04; 139(1). PMID: 27372564
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NK-92: an 'off-the-shelf therapeutic' for adoptive natural killer cell-based cancer immunotherapy.
Garnet Suck, Marcus Odendahl, +4 authors, Torsten Tonn.
Cancer Immunol Immunother, 2015 Nov 13; 65(4). PMID: 26559813
Highly Cited. Review.
The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody.
Don M Benson, Courtney E Bakan, +14 authors, Michael A Caligiuri.
Blood, 2010 May 13; 116(13). PMID: 20460501    Free PMC article.
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Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G.
Mitsunori Shiroishi, Kouhei Tsumoto, +11 authors, Katsumi Maenaka.
Proc Natl Acad Sci U S A, 2003 Jul 11; 100(15). PMID: 12853576    Free PMC article.
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CAR T Cells in Trials: Recent Achievements and Challenges that Remain in the Production of Modified T Cells for Clinical Applications.
Ulrike Köhl, Stanislava Arsenieva, Astrid Holzinger, Hinrich Abken.
Hum Gene Ther, 2018 Apr 06; 29(5). PMID: 29620951
Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition.
Jiangtao Ren, Xiaojun Liu, +3 authors, Yangbing Zhao.
Clin Cancer Res, 2016 Nov 07; 23(9). PMID: 27815355    Free PMC article.
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Targeting NK Cells for Anticancer Immunotherapy: Clinical and Preclinical Approaches.
Sebastian Carotta.
Front Immunol, 2016 May 06; 7. PMID: 27148271    Free PMC article.
DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy.
Katrin Töpfer, Marc Cartellieri, +7 authors, Achim Temme.
J Immunol, 2015 Mar 06; 194(7). PMID: 25740942
CAR-NK for tumor immunotherapy: Clinical transformation and future prospects.
Wenxiu Wang, Jingting Jiang, Changping Wu.
Cancer Lett, 2019 Dec 04; 472. PMID: 31790761
The basic principles of chimeric antigen receptor design.
Michel Sadelain, Renier Brentjens, Isabelle Rivière.
Cancer Discov, 2013 Apr 04; 3(4). PMID: 23550147    Free PMC article.
Highly Cited. Review.
NK cell-based immunotherapy for malignant diseases.
Min Cheng, Yongyan Chen, +2 authors, Zhigang Tian.
Cell Mol Immunol, 2013 Apr 23; 10(3). PMID: 23604045    Free PMC article.
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The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.
Robert J Johnston, Laetitia Comps-Agrar, +9 authors, Jane L Grogan.
Cancer Cell, 2014 Dec 04; 26(6). PMID: 25465800
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A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer.
Michael H Kershaw, Jennifer A Westwood, +11 authors, Patrick Hwu.
Clin Cancer Res, 2006 Oct 26; 12(20 Pt 1). PMID: 17062687    Free PMC article.
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CD33 (Siglec-3) Inhibitory Function: Role in the NKG2D/DAP10 Activating Pathway.
Trinidad Hernández-Caselles, Rubén Corral-San Miguel, Antonio José Ruiz-Alcaraz, Pilar García-Peñarrubia.
J Immunol Res, 2019 May 31; 2019. PMID: 31143782    Free PMC article.
Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming.
Aimee Merino, Bin Zhang, +5 authors, Frank Cichocki.
J Clin Invest, 2019 Jun 19; 129(9). PMID: 31211698    Free PMC article.
Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity.
Ye Li, David L Hermanson, Branden S Moriarity, Dan S Kaufman.
Cell Stem Cell, 2018 Aug 08; 23(2). PMID: 30082067    Free PMC article.
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Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor.
Christiane Sahm, Kurt Schönfeld, Winfried S Wels.
Cancer Immunol Immunother, 2012 Feb 09; 61(9). PMID: 22310931
CD28 costimulation Impairs the efficacy of a redirected t-cell antitumor attack in the presence of regulatory t cells which can be overcome by preventing Lck activation.
David M Kofler, Markus Chmielewski, +6 authors, Hinrich Abken.
Mol Ther, 2011 Feb 18; 19(4). PMID: 21326215    Free PMC article.
Immunometabolic Dysfunction of Natural Killer Cells Mediated by the Hypoxia-CD73 Axis in Solid Tumors.
Andrea M Chambers, Sandro Matosevic.
Front Mol Biosci, 2019 Aug 10; 6. PMID: 31396523    Free PMC article.
Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
Manu Rangachari, Chen Zhu, +13 authors, Vijay K Kuchroo.
Nat Med, 2012 Aug 07; 18(9). PMID: 22863785    Free PMC article.
Highly Cited.
The critical role of residues 43R and 44Q of carcinoembryonic antigen cell adhesion molecules-1 in the protection from killing by human NK cells.
Gal Markel, Raizy Gruda, +6 authors, Ofer Mandelboim.
J Immunol, 2004 Sep 10; 173(6). PMID: 15356119
Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity.
Christopher C Stebbins, Carsten Watzl, +3 authors, Eric O Long.
Mol Cell Biol, 2003 Aug 15; 23(17). PMID: 12917349    Free PMC article.
A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission.
Norbert Vey, Jean-Henri Bourhis, +9 authors, Daniel Olive.
Blood, 2012 Sep 25; 120(22). PMID: 23002117
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Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3.
Jun Wang, Miguel F Sanmamed, +18 authors, Lieping Chen.
Cell, 2018 Dec 26; 176(1-2). PMID: 30580966    Free PMC article.
Highly Cited.
Minimal PD-1 expression in mouse and human NK cells under diverse conditions.
Sean J Judge, Cordelia Dunai, +13 authors, William J Murphy.
J Clin Invest, 2020 Mar 07; 130(6). PMID: 32134744    Free PMC article.
Reversal of natural killer cell exhaustion by TIM-3 blockade.
Anne Gallois, Ines Silva, Iman Osman, Nina Bhardwaj.
Oncoimmunology, 2015 May 13; 3(12). PMID: 25964857    Free PMC article.
Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion.
Jason E Hudak, Stephen M Canham, Carolyn R Bertozzi.
Nat Chem Biol, 2013 Dec 03; 10(1). PMID: 24292068    Free PMC article.
Highly Cited.
Controlling natural killer cell responses: integration of signals for activation and inhibition.
Eric O Long, Hun Sik Kim, +2 authors, Sumati Rajagopalan.
Annu Rev Immunol, 2013 Mar 23; 31. PMID: 23516982    Free PMC article.
Highly Cited. Review.
The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets.
Bertrand Allard, Maria Serena Longhi, Simon C Robson, John Stagg.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258700    Free PMC article.
Highly Cited. Review.
CRISPR-Cas9-mediated multiplex gene editing in CAR-T cells.
Xiaojuan Liu, Yongping Zhang, +7 authors, Haoyi Wang.
Cell Res, 2016 Dec 03; 27(1). PMID: 27910851    Free PMC article.
Highly Cited.
Enhancing a Natural Killer: Modification of NK Cells for Cancer Immunotherapy.
Rasa Islam, Aleta Pupovac, +4 authors, Alan Trounson.
Cells, 2021 May 06; 10(5). PMID: 33946954    Free PMC article.
The "Magic Bullet" Is Here? Cell-Based Immunotherapies for Hematological Malignancies in the Twilight of the Chemotherapy Era.
Nina Miazek-Zapala, Aleksander Slusarczyk, +4 authors, Malgorzata Bobrowicz.
Cells, 2021 Jul 03; 10(6). PMID: 34203935    Free PMC article.
Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges.
Alessandro Poggi, Maria Raffaella Zocchi.
Mol Ther Oncolytics, 2022 Jan 04; 24. PMID: 34977340    Free PMC article.