The Early Expansion of Anergic NKG2A/CD56/CD16 Natural Killer Represents a Therapeutic Target in Haploidentical Hematopoietic Stem Cell Transplantation

Overview

Journal Haematologica

Specialty Hematology

Date 2018 Apr 28

PMID 29700172

Citations 40

Authors

Alessandra Roberto

Clara Di Vito

Elisa Zaghi

Emilia Maria Cristina Mazza

Arianna Capucetti

Michela Calvi

Paolo Tentorio

Veronica Zanon

Barbara Sarina

Jacopo Mariotti

Stefania Bramanti

Elena Tenedini

Enrico Tagliafico

Silvio Bicciato

Armando Santoro

Mario Roederer

Emanuela Marcenaro

Luca Castagna

Enrico Lugli

Domenico Mavilio

Affiliations

Soon will be listed here.

Abstract

Natural killer cells are the first lymphocyte population to reconstitute early after non-myeloablative and T cell-replete haploidentical hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The study herein characterizes the transient and predominant expansion starting from the second week following haploidentical hematopoietic stem cell transplantation of a donor-derived unconventional subset of NKp46/CD56/CD16 natural killer cells expressing remarkably high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46/CD56/CD16 cells are a distinct natural killer cell subpopulation with features of late stage differentiation, yet retaining proliferative capability and functional plasticity to generate conventional NKp46/CD56/CD16 cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46/CD56/CD16 cells are greatly expanded in the seven weeks following haploidentical hematopoietic stem cell transplantation, and express high levels of the activating receptors NKG2D and NKp30 as well as of the lytic granules Granzyme-B and Perforin. Nonetheless, NKp46/CD56/CD16 cells displayed a markedly defective cytotoxicity that could be reversed by blocking the inhibitory receptor CD94/NKG2A. These data open new and important perspectives to better understand the ontogenesis/homeostasis of human natural killer cells and to develop a novel immune-therapeutic approach that targets the inhibitory NKG2A check-point, thus unleashing natural killer cell alloreactivity early after haploidentical hematopoietic stem cell transplantation.

Citing Articles

The diversity of natural killer cell functional and phenotypic states in cancer.

Rishabh K, Matosevic S Cancer Metastasis Rev. 2025; 44(1):26.

PMID: 39853430 DOI: 10.1007/s10555-025-10242-w.

Prognostic significance of early nk cell recovery in pediatric t-cell replete allogeneic hematopoietic stem cell transplantation.

Cui K, Zhang S, Wang Q, Wei Y, Li J Ann Hematol. 2024; 103(12):5769-5780.

PMID: 39549054 DOI: 10.1007/s00277-024-06084-1.

Unlocking the therapeutic potential of the NKG2A-HLA-E immune checkpoint pathway in T cells and NK cells for cancer immunotherapy.

Li Y, Li Z, Tang Y, Zhuang X, Feng W, Boor P J Immunother Cancer. 2024; 12(10).

PMID: 39486805 PMC: 11529472. DOI: 10.1136/jitc-2024-009934.

N-803, an IL-15 Superagonist Complex as Maintenance Therapy After Allogeneic Donor Stem Cell Transplant for Acute Myeloid Leukemia or Myelodysplastic Syndrome; A Phase 2 Trial.

Merino A, Brunstein C, Shanley R, Rashid F, Wangen R, Bachanova V Transplant Cell Ther. 2024; 30(12):1206.e1-1206.e12.

PMID: 39362494 PMC: 11887273. DOI: 10.1016/j.jtct.2024.09.023.

Defects in NK cell immunity of pediatric cancer patients revealed by deep immune profiling.

Syrimi E, Khan N, Murray P, Willcox C, Haigh T, Willcox B iScience. 2024; 27(9):110837.

PMID: 39310750 PMC: 11416690. DOI: 10.1016/j.isci.2024.110837.

References

Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, Cieri N . NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Blood. 2017; 131(2):247-262. PMC: 5757695. DOI: 10.1182/blood-2017-05-780668. View

Imamura M, Tanaka J . Immunoregulatory cells for transplantation tolerance and graft-versus-leukemia effect. Int J Hematol. 2003; 78(3):188-94. DOI: 10.1007/BF02983794. View

Dulphy N, Haas P, Busson M, Belhadj S, Peffault de Latour R, Robin M . An unusual CD56(bright) CD16(low) NK cell subset dominates the early posttransplant period following HLA-matched hematopoietic stem cell transplantation. J Immunol. 2008; 181(3):2227-37. DOI: 10.4049/jimmunol.181.3.2227. View

Boissel L, Tuncer H, Betancur M, Wolfberg A, Klingemann H . Umbilical cord mesenchymal stem cells increase expansion of cord blood natural killer cells. Biol Blood Marrow Transplant. 2008; 14(9):1031-1038. DOI: 10.1016/j.bbmt.2008.06.016. View

Castagna L, Mavilio D . Re-discovering NK cell allo-reactivity in the therapy of solid tumors. J Immunother Cancer. 2016; 4:54. PMC: 5028947. DOI: 10.1186/s40425-016-0159-4. View

Lajoie L, Congy-Jolivet N, Bolzec A, Gouilleux-Gruart V, Sicard E, Sung H . ADAM17-mediated shedding of FcγRIIIA on human NK cells: identification of the cleavage site and relationship with activation. J Immunol. 2013; 192(2):741-51. DOI: 10.4049/jimmunol.1301024. View

Gupta N, Arthos J, Khazanie P, Steenbeke T, Censoplano N, Chung E . Targeted lysis of HIV-infected cells by natural killer cells armed and triggered by a recombinant immunoglobulin fusion protein: implications for immunotherapy. Virology. 2005; 332(2):491-7. DOI: 10.1016/j.virol.2004.12.018. View

Castagna L, Crocchiolo R, Furst S, Bramanti S, El Cheikh J, Sarina B . Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post-transplantation cyclophosphamide. Biol Blood Marrow Transplant. 2014; 20(5):724-9. DOI: 10.1016/j.bbmt.2014.02.001. View

Moretta L, Locatelli F, Pende D, Marcenaro E, Mingari M, Moretta A . Killer Ig-like receptor-mediated control of natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation. Blood. 2010; 117(3):764-71. DOI: 10.1182/blood-2010-08-264085. View

10.

Melenhorst J, Tian X, Xu D, Sandler N, Scheinberg P, Biancotto A . Cytopenia and leukocyte recovery shape cytokine fluctuations after myeloablative allogeneic hematopoietic stem cell transplantation. Haematologica. 2011; 97(6):867-73. PMC: 3366652. DOI: 10.3324/haematol.2011.053363. View

11.

Lugli E, Marcenaro E, Mavilio D . NK Cell Subset Redistribution during the Course of Viral Infections. Front Immunol. 2014; 5:390. PMC: 4132273. DOI: 10.3389/fimmu.2014.00390. View

12.

Hosseini E, Ghasemzadeh M, Kamalizad M, Schwarer A . Ex vivo expansion of CD3 cord blood-MNCs in the presence of bone marrow stromal cells; an appropriate strategy to provide functional NK cells applicable for cellular therapy. Stem Cell Res. 2017; 19:148-155. DOI: 10.1016/j.scr.2017.01.010. View

13.

Scoville S, Freud A, Caligiuri M . Modeling Human Natural Killer Cell Development in the Era of Innate Lymphoid Cells. Front Immunol. 2017; 8:360. PMC: 5366880. DOI: 10.3389/fimmu.2017.00360. View

14.

Novick D, Kim S, Kaplanski G, Dinarello C . Interleukin-18, more than a Th1 cytokine. Semin Immunol. 2013; 25(6):439-48. DOI: 10.1016/j.smim.2013.10.014. View

15.

Fan Y, Yang B, Wu C . Phenotypically and functionally distinct subsets of natural killer cells in human PBMCs. Cell Biol Int. 2007; 32(2):188-97. DOI: 10.1016/j.cellbi.2007.08.025. View

16.

Romee R, Foley B, Lenvik T, Wang Y, Zhang B, Ankarlo D . NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood. 2013; 121(18):3599-608. PMC: 3643761. DOI: 10.1182/blood-2012-04-425397. View

17.

Raiola A, Dominietto A, Varaldo R, Ghiso A, Galaverna F, Bramanti S . Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin's lymphoma. Bone Marrow Transplant. 2013; 49(2):190-4. DOI: 10.1038/bmt.2013.166. View

18.

Yu J, Freud A, Caligiuri M . Location and cellular stages of natural killer cell development. Trends Immunol. 2013; 34(12):573-82. PMC: 3852183. DOI: 10.1016/j.it.2013.07.005. View

19.

Wagner J, Rosario M, Romee R, Berrien-Elliott M, Schneider S, Leong J . CD56bright NK cells exhibit potent antitumor responses following IL-15 priming. J Clin Invest. 2017; 127(11):4042-4058. PMC: 5663359. DOI: 10.1172/JCI90387. View

20.

Roberto A, Castagna L, Gandolfi S, Zanon V, Bramanti S, Sarina B . B-cell reconstitution recapitulates B-cell lymphopoiesis following haploidentical BM transplantation and post-transplant CY. Bone Marrow Transplant. 2014; 50(2):317-9. DOI: 10.1038/bmt.2014.266. View