Killer Instincts: Natural Killer Cells As Multifactorial Cancer Immunotherapy

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Dec 13

PMID 38090565

Authors

Sarah Nersesian

Emily B Carter

Stacey N Lee

Lauren P Westhaver

Jeanette E Boudreau

Affiliations

Soon will be listed here.

Abstract

Natural killer (NK) cells integrate heterogeneous signals for activation and inhibition using germline-encoded receptors. These receptors are stochastically co-expressed, and their concurrent engagement and signaling can adjust the sensitivity of individual cells to putative targets. Against cancers, which mutate and evolve under therapeutic and immunologic pressure, the diversity for recognition provided by NK cells may be key to comprehensive cancer control. NK cells are already being trialled as adoptive cell therapy and targets for immunotherapeutic agents. However, strategies to leverage their naturally occurring diversity and agility have not yet been developed. In this review, we discuss the receptors and signaling pathways through which signals for activation or inhibition are generated in NK cells, focusing on their roles in cancer and potential as targets for immunotherapies. Finally, we consider the impacts of receptor co-expression and the potential to engage multiple pathways of NK cell reactivity to maximize the scope and strength of antitumor activities.

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References

Sivori S, Pende D, Bottino C, Marcenaro E, Pessino A, Biassoni R . NKp46 is the major triggering receptor involved in the natural cytotoxicity of fresh or cultured human NK cells. Correlation between surface density of NKp46 and natural cytotoxicity against autologous, allogeneic or xenogeneic target cells. Eur J Immunol. 1999; 29(5):1656-66. DOI: 10.1002/(SICI)1521-4141(199905)29:05<1656::AID-IMMU1656>3.0.CO;2-1. View

Zhang R, Cui D, Xue T, Lang Y, Zhang Y, Li L . HLA-B-associated transcript 3 (Bat3) stabilizes and activates p53 in a HAUSP-dependent manner. J Mol Cell Biol. 2019; 12(2):99-112. PMC: 7109604. DOI: 10.1093/jmcb/mjz102. View

Oleary L, van der Sloot A, Reis C, Deegan S, Ryan A, Dhami S . Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity. Oncogene. 2015; 35(10):1261-70. DOI: 10.1038/onc.2015.180. View

Beziat V, Dalgard O, Asselah T, Halfon P, Bedossa P, Boudifa A . CMV drives clonal expansion of NKG2C+ NK cells expressing self-specific KIRs in chronic hepatitis patients. Eur J Immunol. 2011; 42(2):447-57. DOI: 10.1002/eji.201141826. View

Jiao J, Jiao D, Yang F, Zhang J, Li Y, Han D . Galectin-9 expression predicts poor prognosis in hepatitis B virus-associated hepatocellular carcinoma. Aging (Albany NY). 2022; 14(4):1879-1890. PMC: 8908941. DOI: 10.18632/aging.203909. View

Pogge von Strandmann E, Simhadri V, von Tresckow B, Sasse S, Reiners K, Hansen H . Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity. 2007; 27(6):965-74. DOI: 10.1016/j.immuni.2007.10.010. View

Mansour A, Raucci F, Sevim M, Saviano A, Begum J, Zhi Z . Galectin-9 supports primary T cell transendothelial migration in a glycan and integrin dependent manner. Biomed Pharmacother. 2022; 151:113171. DOI: 10.1016/j.biopha.2022.113171. View

Miao X, Yang Z, Xiong L, Zou Q, Yuan Y, Li J . Nectin-2 and DDX3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinoma of gallbladder. Int J Clin Exp Pathol. 2013; 6(2):179-90. PMC: 3544223. View

Zhang X, Wu T, Cai X, Dong J, Xia C, Zhou Y . Neoadjuvant Immunotherapy for MSI-H/dMMR Locally Advanced Colorectal Cancer: New Strategies and Unveiled Opportunities. Front Immunol. 2022; 13:795972. PMC: 8968082. DOI: 10.3389/fimmu.2022.795972. View

10.

Demaria O, Gauthier L, Vetizou M, Alvarez A, Vagne C, Habif G . Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant. Cell Rep Med. 2022; 3(10):100783. PMC: 9589122. DOI: 10.1016/j.xcrm.2022.100783. View

11.

Ashour R, Ri M, Aly S, Yoshida T, Tachita T, Kanamori T . Expression analysis of two SLAM family receptors, SLAMF2 and SLAMF7, in patients with multiple myeloma. Int J Hematol. 2019; 110(1):69-76. DOI: 10.1007/s12185-019-02649-3. View

12.

Dulberger C, McMurtrey C, Holzemer A, Neu K, Liu V, Steinbach A . Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors. Immunity. 2017; 46(6):1018-1029.e7. PMC: 5523829. DOI: 10.1016/j.immuni.2017.06.002. View

13.

Ndhlovu L, Lopez-Verges S, Barbour J, Jones R, Jha A, Long B . Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood. 2012; 119(16):3734-43. PMC: 3335380. DOI: 10.1182/blood-2011-11-392951. View

14.

Liu J, Qian X, Chen Z, Xu X, Gao F, Zhang S . Crystal structure of cell adhesion molecule nectin-2/CD112 and its binding to immune receptor DNAM-1/CD226. J Immunol. 2012; 188(11):5511-20. DOI: 10.4049/jimmunol.1200324. View

15.

Poggi A, Zocchi M . Natural killer cells and immune-checkpoint inhibitor therapy: Current knowledge and new challenges. Mol Ther Oncolytics. 2022; 24:26-42. PMC: 8693432. DOI: 10.1016/j.omto.2021.11.016. View

16.

Cichocki F, Bjordahl R, Goodridge J, Mahmood S, Gaidarova S, Abujarour R . Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma. Nat Commun. 2022; 13(1):7341. PMC: 9709157. DOI: 10.1038/s41467-022-35127-2. View

17.

Pesini C, Hidalgo S, Arias M, Santiago L, Calvo C, Ocariz-Diez M . PD-1 is expressed in cytotoxic granules of NK cells and rapidly mobilized to the cell membrane following recognition of tumor cells. Oncoimmunology. 2022; 11(1):2096359. PMC: 9262365. DOI: 10.1080/2162402X.2022.2096359. View

18.

Clynes R, Towers T, Presta L, Ravetch J . Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000; 6(4):443-6. DOI: 10.1038/74704. View

19.

McGranahan N, Rosenthal R, Hiley C, Rowan A, Watkins T, Wilson G . Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. Cell. 2017; 171(6):1259-1271.e11. PMC: 5720478. DOI: 10.1016/j.cell.2017.10.001. View

20.

Tarek N, Le Luduec J, Gallagher M, Zheng J, Venstrom J, Chamberlain E . Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J Clin Invest. 2012; 122(9):3260-70. PMC: 3428088. DOI: 10.1172/JCI62749. View