Natural Killer Cells in Neuroblastoma: Immunological Insights and Therapeutic Perspectives

Overview

Journal Cancer Metastasis Rev

Specialty Oncology

Date 2024 Sep 18

PMID 39294470

Authors

Magdalena Rados

Anna Landegger

Lukas Schmutzler

Kimberlie Rabidou

Sabine Taschner-Mandl

Irfete S Fetahu

Affiliations

Soon will be listed here.

Abstract

Natural killer (NK) cells have multifaceted roles within the complex tumor milieu. They are pivotal components of innate immunity and shape the dynamic landscape of tumor-immune cell interactions, and thus can be leveraged for use in therapeutic interventions. NK-based immunotherapies have had remarkable success in hematological malignancies, but these therapies are met with many challenges in solid tumors, including neuroblastoma (NB), a childhood tumor arising from the sympathetic nervous system. With a focus on NB, this review outlines the mechanisms employed by NK cells to recognize and eliminate malignant cells, delving into the dynamic relationship between ligand-receptor interactions, cytokines, and other molecules that facilitate the cross talk between NK and NB cells. We discuss the immunomodulatory functions of NK cells and the mechanisms that contribute to loss of this immunosurveillance in NB, with a focus on how this dynamic has been utilized in recent immunotherapy advancements for NB.

Citing Articles

Association of Neuroblastoma (NB) SH-SY5Y Cells with Antibodies of Parasitic Origin (Anti- and Anti-).

Maravelez Acosta V, Garcia M, Patino Lopez G, Crisostomo Vazquez M, Franco Sandoval L, Eligio Garcia L Int J Mol Sci. 2025; 25(24.

PMID: 39769340 PMC: 11678856. DOI: 10.3390/ijms252413577.

References

Shusterman S, Naranjo A, Van Ryn C, Hank J, Parisi M, Shulkin B . Antitumor Activity and Tolerability of hu14.18-IL2 with GMCSF and Isotretinoin in Recurrent or Refractory Neuroblastoma: A Children's Oncology Group Phase II Study. Clin Cancer Res. 2019; 25(20):6044-6051. PMC: 6945765. DOI: 10.1158/1078-0432.CCR-19-0798. View

Ladenstein R, Potschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I . Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018; 19(12):1617-1629. DOI: 10.1016/S1470-2045(18)30578-3. View

Van de Velde L, Allen E, Crawford J, Wilson T, Guy C, Russier M . Neuroblastoma Formation Requires Unconventional CD4 T Cells and Arginase-1-Dependent Myeloid Cells. Cancer Res. 2021; 81(19):5047-5059. PMC: 8488023. DOI: 10.1158/0008-5472.CAN-21-0691. View

Egler R, Burlingame S, Nuchtern J, Russell H . Interleukin-6 and soluble interleukin-6 receptor levels as markers of disease extent and prognosis in neuroblastoma. Clin Cancer Res. 2008; 14(21):7028-34. PMC: 2613275. DOI: 10.1158/1078-0432.CCR-07-5017. View

Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B . Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J Exp Med. 2003; 198(4):557-67. PMC: 2194180. DOI: 10.1084/jem.20030788. View

Lanier L . Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008; 9(5):495-502. PMC: 2669298. DOI: 10.1038/ni1581. View

Morandi F, Pozzi S, Carlini B, Amoroso L, Pistoia V, Corrias M . Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients. J Immunol Res. 2016; 2016:7465741. PMC: 5004009. DOI: 10.1155/2016/7465741. View

George R, Li S, Medeiros-Nancarrow C, Neuberg D, Marcus K, Shamberger R . High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol. 2006; 24(18):2891-6. DOI: 10.1200/JCO.2006.05.6986. View

Wu J, Song Y, Bakker A, Bauer S, Spies T, Lanier L . An activating immunoreceptor complex formed by NKG2D and DAP10. Science. 1999; 285(5428):730-2. DOI: 10.1126/science.285.5428.730. View

10.

Wienke J, Visser L, Kholosy W, Keller K, Barisa M, Poon E . Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy. Cancer Cell. 2024; 42(2):283-300.e8. PMC: 10864003. DOI: 10.1016/j.ccell.2023.12.008. View

11.

Tesi B, Schlums H, Cichocki F, Bryceson Y . Epigenetic Regulation of Adaptive NK Cell Diversification. Trends Immunol. 2016; 37(7):451-461. DOI: 10.1016/j.it.2016.04.006. View

12.

Vincent M, Bessard A, Cochonneau D, Teppaz G, Sole V, Maillasson M . Tumor targeting of the IL-15 superagonist RLI by an anti-GD2 antibody strongly enhances its antitumor potency. Int J Cancer. 2013; 133(3):757-65. DOI: 10.1002/ijc.28059. View

13.

Markham A . Naxitamab: First Approval. Drugs. 2021; 81(2):291-296. DOI: 10.1007/s40265-021-01467-4. View

14.

Tran H, Wan Z, Sheard M, Sun J, Jackson J, Malvar J . TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells. Clin Cancer Res. 2016; 23(3):804-813. PMC: 5361893. DOI: 10.1158/1078-0432.CCR-16-1743. View

15.

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

16.

Zamai L, Ahmad M, M Bennett I, Azzoni L, Alnemri E, Perussia B . Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. J Exp Med. 1998; 188(12):2375-80. PMC: 2212426. DOI: 10.1084/jem.188.12.2375. View

17.

Talleur A, Triplett B, Federico S, Mamcarz E, Janssen W, Wu J . Consolidation Therapy for Newly Diagnosed Pediatric Patients with High-Risk Neuroblastoma Using Busulfan/Melphalan, Autologous Hematopoietic Cell Transplantation, Anti-GD2 Antibody, Granulocyte-Macrophage Colony-Stimulating Factor, Interleukin-2,.... Biol Blood Marrow Transplant. 2017; 23(11):1910-1917. PMC: 5682204. DOI: 10.1016/j.bbmt.2017.07.011. View

18.

Zobel M, Zamora A, Wu H, Sun J, Lascano D, Malvar J . Initiation of immunotherapy with activated natural killer cells and anti-GD2 antibody dinutuximab prior to resection of primary neuroblastoma prolongs survival in mice. J Immunother Cancer. 2021; 8(2). PMC: 7751216. DOI: 10.1136/jitc-2020-001560. View

19.

Voeller J, Erbe A, Slowinski J, Rasmussen K, Carlson P, Hoefges A . Combined innate and adaptive immunotherapy overcomes resistance of immunologically cold syngeneic murine neuroblastoma to checkpoint inhibition. J Immunother Cancer. 2019; 7(1):344. PMC: 6898936. DOI: 10.1186/s40425-019-0823-6. View

20.

Layer J, Kronmuller M, Quast T, van den Boorn-Konijnenberg D, Effern M, Hinze D . Amplification of N-Myc is associated with a T-cell-poor microenvironment in metastatic neuroblastoma restraining interferon pathway activity and chemokine expression. Oncoimmunology. 2017; 6(6):e1320626. PMC: 5486176. DOI: 10.1080/2162402X.2017.1320626. View