Review
. 2018 Sep; 9:2041.
doi: 10.3389/fimmu.2018.02041.

Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells

Nayoung Kim 1 Hun Sik Kim 2 
Affiliations
  • PMID: 30250471
  •     129 References
  •     50 citations

Abstract

Among the most promising therapeutic modalities for cancer treatment is the blockade of immune checkpoint pathways, which are frequently co-opted by tumors as a major mechanism of immune escape. CTLA-4 and PD-1 are the representative examples, and their blockade by therapeutic antibodies leads to enhanced anti-tumor immunity with durable clinical responses, but only in a minority of patients. This has highlighted the need to identify and target additional immune checkpoints that can be exploited to further enhance immune responses to refractory cancers. These emerging targets include natural killer (NK) cell-directed checkpoint receptors (KIR and CD94/NKG2A) as well as the NK- and T cell-expressed checkpoints TIM-3, TIGIT, CD96, and LAG-3. Interestingly, the potentiation of anti-tumor immunity by checkpoint blockade relies not only on T cells but also on other components of the innate immune system, including NK cells. NK cells are innate lymphoid cells that efficiently kill tumor cells without MHC specificity, which is complementary to the MHC-restricted tumor lysis mediated by cytotoxic T cells. However, the role of these immune checkpoints in modulating the function of NK cells remains unclear and somewhat controversial. Unraveling the mechanisms by which these immune checkpoints function in NK cells and other immune cells will pave the way to developing new therapeutic strategies to optimize anti-tumor immunity while limiting cancer immune escape. Here, we focus on recent findings regarding the roles of immune checkpoints in regulating NK cell function and their potential application in cancer immunotherapy.

Keywords: NK cells; cancer immunotherapy; checkpoint blockade; combined targeting; immune checkpoints.

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Mattias Carlsten, Neha Korde, +5 authors, Richard W Childs.
Clin Cancer Res, 2016 Nov 03; 22(21). PMID: 27307594    Free PMC article.
Highly Cited.
Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family.
Frank A Schildberg, Sarah R Klein, Gordon J Freeman, Arlene H Sharpe.
Immunity, 2016 May 19; 44(5). PMID: 27192563    Free PMC article.
Highly Cited. Review.
Profound coordinated alterations of intratumoral NK cell phenotype and function in lung carcinoma.
Sophia Platonova, Julien Cherfils-Vicini, +10 authors, Isabelle Cremer.
Cancer Res, 2011 Jun 29; 71(16). PMID: 21708957
Highly Cited.
The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity.
Noa Stanietsky, Hrvoje Simic, +11 authors, Ofer Mandelboim.
Proc Natl Acad Sci U S A, 2009 Oct 10; 106(42). PMID: 19815499    Free PMC article.
Highly Cited.
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.
Highly Cited.
Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies.
Holbrook E Kohrt, Ariane Thielens, +14 authors, Pascale André.
Blood, 2013 Dec 12; 123(5). PMID: 24326534    Free PMC article.
Highly Cited.
Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity.
Lishomwa C Ndhlovu, Sandra Lopez-Vergès, +7 authors, Lewis L Lanier.
Blood, 2012 Mar 03; 119(16). PMID: 22383801    Free PMC article.
Highly Cited.
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.
James Larkin, Vanna Chiarion-Sileni, +28 authors, Jedd D Wolchok.
N Engl J Med, 2015 Jun 02; 373(1). PMID: 26027431    Free PMC article.
Highly Cited.
Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape.
Janis M Taube, Robert A Anders, +8 authors, Lieping Chen.
Sci Transl Med, 2012 Mar 31; 4(127). PMID: 22461641    Free PMC article.
Highly Cited.
Up on the tightrope: natural killer cell activation and inhibition.
Lewis L Lanier.
Nat Immunol, 2008 Apr 22; 9(5). PMID: 18425106    Free PMC article.
Highly Cited. Review.
PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma.
Asma Beldi-Ferchiou, Marion Lambert, +10 authors, Sophie Caillat-Zucman.
Oncotarget, 2016 Sep 24; 7(45). PMID: 27662664    Free PMC article.
Highly Cited.
Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.
Haidong Dong, Scott E Strome, +10 authors, Lieping Chen.
Nat Med, 2002 Jul 02; 8(8). PMID: 12091876
Highly Cited.
Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia.
Emily M McWilliams, Jennifer M Mele, +7 authors, Farrukh T Awan.
Oncoimmunology, 2016 Nov 18; 5(10). PMID: 27853650    Free PMC article.
Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade.
Yoshiko Iwai, Masayoshi Ishida, +3 authors, Nagahiro Minato.
Proc Natl Acad Sci U S A, 2002 Sep 10; 99(19). PMID: 12218188    Free PMC article.
Highly Cited.
LAG-3, a novel lymphocyte activation gene closely related to CD4.
F Triebel, S Jitsukawa, +4 authors, T Hercend.
J Exp Med, 1990 May 01; 171(5). PMID: 1692078    Free PMC article.
Highly Cited.
Features of Memory-Like and PD-1(+) Human NK Cell Subsets.
Mariella Della Chiesa, Silvia Pesce, +4 authors, Emanuela Marcenaro.
Front Immunol, 2016 Sep 30; 7. PMID: 27683578    Free PMC article.
Highly Cited. Review.
Negative regulation of lymphocyte development and function by the Cbl family of proteins.
Fang Huang, Hua Gu.
Immunol Rev, 2008 Sep 02; 224. PMID: 18759930
Review.
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
Kaori Sakuishi, Lionel Apetoh, +3 authors, Ana C Anderson.
J Exp Med, 2010 Sep 08; 207(10). PMID: 20819927    Free PMC article.
Highly Cited.
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.
Highly Cited.
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.
Julie R Brahmer, Scott S Tykodi, +23 authors, Jon M Wigginton.
N Engl J Med, 2012 Jun 05; 366(26). PMID: 22658128    Free PMC article.
Highly Cited.
Balancing natural killer cell activation through paired receptors.
Ludovic Martinet, Mark J Smyth.
Nat Rev Immunol, 2015 Mar 07; 15(4). PMID: 25743219
Highly Cited. Review.
Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma.
Niels W C J van de Donk, Philippe Moreau, +9 authors, Paul G Richardson.
Blood, 2015 Dec 04; 127(6). PMID: 26631114
Highly Cited. Review.
The adaptor protein Crk controls activation and inhibition of natural killer cells.
Dongfang Liu, Mary E Peterson, Eric O Long.
Immunity, 2012 Apr 03; 36(4). PMID: 22464172    Free PMC article.
Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule.
Cristina Bottino, Roberta Castriconi, +11 authors, Alessandro Moretta.
J Exp Med, 2003 Aug 13; 198(4). PMID: 12913096    Free PMC article.
Highly Cited.
CIS is a potent checkpoint in NK cell-mediated tumor immunity.
Rebecca B Delconte, Tatiana B Kolesnik, +29 authors, Nicholas D Huntington.
Nat Immunol, 2016 May 24; 17(7). PMID: 27213690
Highly Cited.
Human NK cells: surface receptors, inhibitory checkpoints, and translational applications.
Simona Sivori, Paola Vacca, +3 authors, Lorenzo Moretta.
Cell Mol Immunol, 2019 Feb 20; 16(5). PMID: 30778167    Free PMC article.
Highly Cited. Review.
The IL-12- and IL-23-Dependent NK Cell Response Is Essential for Protective Immunity against Secondary Toxoplasma gondii Infection.
Daria L Ivanova, Tiffany M Mundhenke, Jason P Gigley.
J Immunol, 2019 Oct 13; 203(11). PMID: 31604804    Free PMC article.
In vitro education of human natural killer cells by KIR3DL1.
Jason Pugh, Neda Nemat-Gorgani, +3 authors, Peter Parham.
Life Sci Alliance, 2019 Nov 15; 2(6). PMID: 31723004    Free PMC article.
Mannan-Binding Lectin Regulates Inflammatory Cytokine Production, Proliferation, and Cytotoxicity of Human Peripheral Natural Killer Cells.
Jia Zhou, Mengyao Hu, +6 authors, Zhengliang Chen.
Mediators Inflamm, 2020 Jan 10; 2019. PMID: 31915415    Free PMC article.
Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors.
Ombretta Melaiu, Valeria Lucarini, Loredana Cifaldi, Doriana Fruci.
Front Immunol, 2020 Feb 11; 10. PMID: 32038612    Free PMC article.
Review.
Blockade of PD-1 and LAG-3 Immune Checkpoints Combined with Vaccination Restores the Function of Antiviral Tissue-Resident CD8+ TRM Cells and Reduces Ocular Herpes Simplex Infection and Disease in HLA Transgenic Rabbits.
Soumyabrata Roy, Pierre-Gregoire Coulon, +11 authors, Lbachir BenMohamed.
J Virol, 2019 Jun 21; 93(18). PMID: 31217250    Free PMC article.
Targeting Natural Killer Cells for Tumor Immunotherapy.
Cai Zhang, Yuan Hu, Chongdeng Shi.
Front Immunol, 2020 Mar 07; 11. PMID: 32140153    Free PMC article.
Review.
Neuroendocrine control of natural killer cell function through the checkpoint molecule PD-1.
Justine Devulder, Anne Tsicopoulos, Catherine Duez.
Cell Mol Immunol, 2018 Nov 24; 16(2). PMID: 30467417    Free PMC article.
Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.
Soumyabrata Roy, Pierre-Grégoire Coulon, +7 authors, Lbachir BenMohamed.
Front Immunol, 2019 Jan 09; 9. PMID: 30619285    Free PMC article.
Unleashing Natural Killer Cells in the Tumor Microenvironment-The Next Generation of Immunotherapy?
Aviad Ben-Shmuel, Guy Biber, Mira Barda-Saad.
Front Immunol, 2020 Mar 11; 11. PMID: 32153582    Free PMC article.
Review.
Cancer Immunotherapy Based on Natural Killer Cells: Current Progress and New Opportunities.
Weilei Hu, Guosheng Wang, +2 authors, Yibing Xu.
Front Immunol, 2019 Jun 20; 10. PMID: 31214177    Free PMC article.
Highly Cited. Review.
The IUPHAR Guide to Immunopharmacology: connecting immunology and pharmacology.
Simon D Harding, Elena Faccenda, +8 authors, Jamie A Davies.
Immunology, 2020 Feb 06; 160(1). PMID: 32020584    Free PMC article.
Review.
Progressive Impairment of NK Cell Cytotoxic Degranulation Is Associated With TGF-β1 Deregulation and Disease Progression in Pancreatic Cancer.
Eunsung Jun, Ah Young Song, +8 authors, Hun Sik Kim.
Front Immunol, 2019 Jul 10; 10. PMID: 31281312    Free PMC article.
In Situ Immune Profiling of Heart Transplant Biopsies Improves Diagnostic Accuracy and Rejection Risk Stratification.
Eliot G Peyster, Chichung Wang, +4 authors, Kenneth B Margulies.
JACC Basic Transl Sci, 2020 May 06; 5(4). PMID: 32368693    Free PMC article.
Overview of Strategies to Improve Therapy against Tumors Using Natural Killer Cell.
Chaopin Yang, Yue Li, Yaozhang Yang, Zhiyi Chen.
J Immunol Res, 2020 May 16; 2020. PMID: 32411806    Free PMC article.
Review.
Targeted Therapies: Friends or Foes for Patient's NK Cell-Mediated Tumor Immune-Surveillance?
Laura Damele, Selene Ottonello, +2 authors, Chiara Vitale.
Cancers (Basel), 2020 Mar 29; 12(4). PMID: 32218226    Free PMC article.
Review.
Inhibitory checkpoints in human natural killer cells: IUPHAR Review 28.
F R Mariotti, L Quatrini, +5 authors, L Moretta.
Br J Pharmacol, 2020 Apr 27; 177(13). PMID: 32335915    Free PMC article.
Review.
Ectopic expression of LAG-3 in non-small-cell lung cancer cells and its clinical significance.
Chenglong Ma, Xiao Sun, +3 authors, Chunjian Qi.
J Clin Lab Anal, 2020 Feb 23; 34(6). PMID: 32077528    Free PMC article.
An Integrative Analysis Reveals the Underlying Association Between CTNNB1 Mutation and Immunotherapy in Hepatocellular Carcinoma.
Zhuomao Mo, Yongdan Wang, +2 authors, Shijun Zhang.
Front Oncol, 2020 Jul 01; 10. PMID: 32596147    Free PMC article.
The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment.
Giuseppa Augello, Maria R Emma, +4 authors, Melchiorre Cervello.
Cells, 2020 Jun 13; 9(6). PMID: 32526891    Free PMC article.
Review.
Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy.
Cai Zhang, Yuxia Liu.
Front Immunol, 2020 Jul 28; 11. PMID: 32714324    Free PMC article.
Review.
Research Progress on NK Cell Receptors and Their Signaling Pathways.
Yingying Chen, Dan Lu, Alexey Churov, Rong Fu.
Mediators Inflamm, 2020 Aug 11; 2020. PMID: 32774149    Free PMC article.
Review.
Characterization of the DNAM-1, TIGIT and TACTILE Axis on Circulating NK, NKT-Like and T Cell Subsets in Patients with Acute Myeloid Leukemia.
Isabel Valhondo, Fakhri Hassouneh, +14 authors, Raquel Tarazona.
Cancers (Basel), 2020 Aug 09; 12(8). PMID: 32764229    Free PMC article.
DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy.
Beatriz Sanchez-Correa, Isabel Valhondo, +10 authors, Raquel Tarazona.
Cancers (Basel), 2019 Jun 27; 11(6). PMID: 31234588    Free PMC article.
Highly Cited. Review.
[Inhibition of CD96 enhances interferon-γ secretion by natural killer cells to alleviate lung injury in mice with pulmonary Chlamydia muridarum infection].
Jing Li, Jing Zheng, +4 authors, Pu Guo.
Nan Fang Yi Ke Da Xue Xue Bao, 2020 Sep 09; 40(7). PMID: 32895152    Free PMC article.
Monoclonal Antibodies in Cancer Therapy.
David Zahavi, Louis Weiner.
Antibodies (Basel), 2020 Jul 24; 9(3). PMID: 32698317    Free PMC article.
Review.
Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy.
Yuqing Cao, Xiaoyu Wang, +5 authors, Feng Xu.
Signal Transduct Target Ther, 2020 Oct 31; 5(1). PMID: 33122640    Free PMC article.
Review.
Cytotoxicity of Human Hepatic Intrasinusoidal CD56bright Natural Killer Cells against Hepatocellular Carcinoma Cells.
Shin Hwang, Jaeseok Han, +7 authors, Nayoung Kim.
Int J Mol Sci, 2019 Mar 31; 20(7). PMID: 30925759    Free PMC article.
Natural Killer Immunotherapy for Minimal Residual Disease Eradication Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia.
Norimichi Hattori, Tsuyoshi Nakamaki.
Int J Mol Sci, 2019 Apr 28; 20(9). PMID: 31027331    Free PMC article.
Review.
DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection?
Loredana Cifaldi, Margherita Doria, +4 authors, Paolo Rossi.
Int J Mol Sci, 2019 Aug 02; 20(15). PMID: 31366013    Free PMC article.
Review.
Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma.
Tatiana Pazina, Alexander W MacFarlane, +8 authors, Adam D Cohen.
Cancers (Basel), 2021 Jan 14; 13(2). PMID: 33435153    Free PMC article.
EZH1/2 Inhibitors Favor ILC3 Development from Human HSPC-CD34+ Cells.
Laura Damele, Adriana Amaro, +4 authors, Chiara Vitale.
Cancers (Basel), 2021 Jan 21; 13(2). PMID: 33467134    Free PMC article.
Dissecting the biology of allogeneic HSCT to enhance the GvT effect whilst minimizing GvHD.
Bruce R Blazar, Geoffrey R Hill, William J Murphy.
Nat Rev Clin Oncol, 2020 Apr 22; 17(8). PMID: 32313224    Free PMC article.
Review.
Natural Killer Cells and Anti-Cancer Therapies: Reciprocal Effects on Immune Function and Therapeutic Response.
Elisa C Toffoli, Abdolkarim Sheikhi, +6 authors, Tanja D de Gruijl.
Cancers (Basel), 2021 Feb 13; 13(4). PMID: 33572396    Free PMC article.
Review.
Analysis of the Characteristics of TIGIT-Expressing CD3-CD56+NK Cells in Controlling Different Stages of HIV-1 Infection.
Xin Zhang, Xiaofan Lu, +11 authors, Bin Su.
Front Immunol, 2021 Mar 16; 12. PMID: 33717085    Free PMC article.
Renaissance of armored immune effector cells, CAR-NK cells, brings the higher hope for successful cancer therapy.
Faroogh Marofi, Heshu Sulaiman Rahman, +11 authors, Farhad Motavalli Khiavi.
Stem Cell Res Ther, 2021 Mar 24; 12(1). PMID: 33752707    Free PMC article.
Review.
NK Cell Adoptive Immunotherapy of Cancer: Evaluating Recognition Strategies and Overcoming Limitations.
Carlos E Sanchez, Ehsan P Dowlati, +4 authors, Conrad Russell Y Cruz.
Transplant Cell Ther, 2020 Oct 03; 27(1). PMID: 33007496    Free PMC article.
Review.
Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy.
Kari A Shaver, Tayler J Croom-Perez, Alicja J Copik.
Front Immunol, 2021 May 18; 12. PMID: 33995422    Free PMC article.
Review.
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.
Review.
Cbl-b Is Upregulated and Plays a Negative Role in Activated Human NK Cells.
Ting Lu, Li Chen, +8 authors, Michael A Caligiuri.
J Immunol, 2021 Jan 10; 206(4). PMID: 33419766    Free PMC article.
The Role of Natural Killer Cells in Soft Tissue Sarcoma: Prospects for Immunotherapy.
Tânia Fortes-Andrade, Jani Sofia Almeida, +4 authors, Paulo Rodrigues-Santos.
Cancers (Basel), 2021 Aug 08; 13(15). PMID: 34359767    Free PMC article.
Review.
PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow.
Ling Xu, Lian Liu, +13 authors, Yangqiu Li.
Front Oncol, 2021 Sep 08; 11. PMID: 34490086    Free PMC article.
The Right Partner in Crime: Unlocking the Potential of the Anti-EGFR Antibody Cetuximab via Combination With Natural Killer Cell Chartering Immunotherapeutic Strategies.
Hasan Baysal, Ines De Pauw, +5 authors, An Wouters.
Front Immunol, 2021 Sep 25; 12. PMID: 34557197    Free PMC article.
Review.
Adipose-Tissue-Derived Mesenchymal Stem Cells Mediate PD-L1 Overexpression in the White Adipose Tissue of Obese Individuals, Resulting in T Cell Dysfunction.
Assia Eljaafari, Julien Pestel, +5 authors, Hubert Vidal.
Cells, 2021 Oct 24; 10(10). PMID: 34685625    Free PMC article.
The Biological Role and Therapeutic Potential of NK Cells in Hematological and Solid Tumors.
Rodion A Velichinskii, Maria A Streltsova, +2 authors, Elena I Kovalenko.
Int J Mol Sci, 2021 Nov 14; 22(21). PMID: 34768814    Free PMC article.
Review.
Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry.
Hee Young Na, Yujun Park, +7 authors, Hye Seung Lee.
J Transl Med, 2021 Dec 26; 19(1). PMID: 34952595    Free PMC article.
CAR-NK Cells: From Natural Basis to Design for Kill.
Muhammad Babar Khawar, Haibo Sun.
Front Immunol, 2022 Jan 01; 12. PMID: 34970253    Free PMC article.
Review.
Role of the tumor immune microenvironment in tumor immunotherapy.
Changsheng Zhou, Qianqian Liu, +2 authors, Wengang Li.
Oncol Lett, 2022 Jan 08; 23(2). PMID: 34992685    Free PMC article.
Review.
IgE-Based Therapeutic Combination Enhances Antitumor Response in Preclinical Models of Pancreatic Cancer.
Spas Dimitrov Markov, Thomas C Caffrey, +21 authors, Kamiya Mehla.
Mol Cancer Ther, 2021 Oct 10; 20(12). PMID: 34625505    Free PMC article.
Adoptive Cell Therapy in Pediatric and Young Adult Solid Tumors: Current Status and Future Directions.
John A Ligon, Kristin M Wessel, Nirali N Shah, John Glod.
Front Immunol, 2022 Mar 12; 13. PMID: 35273619    Free PMC article.
Review.