Page 154 - Haematologica August 2018

Correspondence:
domenico.mavilio@unimi.it or enrico.lugli@humanitasresearch.it
Received: December 16, 2017. Accepted: April 23, 2018. Pre-published: April 26, 2018.
doi:10.3324/haematol.2017.186619
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/8/1390
©2018 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
Haematologica 2018 Volume 103(8):1390-1402
Emanuela Marcenaro,6 Luca Castagna,4 Enrico Lugli1,7* and Domenico
1390
Ferrata Storti Foundation
Cell Therapy & Immunotherapy
The early expansion of anergic NKG2Apos/ CD56dim/CD16neg natural killer represents a therapeutic target in haploidentical hematopoietic stem cell transplantation
Alessandra Roberto,1* Clara Di Vito,2* Elisa Zaghi,2 Emilia Maria Cristina
Mazza,1,3 Arianna Capucetti,2 Michela Calvi,2 Paolo Tentorio,2 Veronica Zanon,1
Barbara Sarina,4 Jacopo Mariotti,4 Stefania Bramanti,4 Elena Tenedini,3
Enrico Tagliafico,3 Silvio Bicciato,3 Armando Santoro,4 Mario Roederer,5
2,8* Mavilio
1Laboratory of Translational Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; 2Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; 3Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 4Bone Marrow Transplant Unit, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; 5ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA; 6Dipartimento di Medicina Sperimentale (DI.ME.S.) and Centro di Eccellenza per le Ricerche Biomediche (CEBR) Università degli Studi di Genova, Italy; 7Humanitas Flow Cytometry Core, Humanitas Clinical and Research Center, Rozzano, Milan, Italy and 8Department of Medical Biotechnologies and Translational Medicine (BioMeTra), University of Milan, Italy
ABSTRACT
Natural killer cells are the first lymphocyte population to reconsti- tute early after non-myeloablative and T cell-replete haploidenti- cal hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The study herein characterizes the tran- sient and predominant expansion starting from the second week follow- ing haploidentical hematopoietic stem cell transplantation of a donor- derived unconventional subset of NKp46neg-low/CD56dim/CD16neg natural killer cells expressing remarkably high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46neg-low/CD56dim/CD16neg cells are a distinct natural killer cell subpop- ulation with features of late stage differentiation, yet retaining prolifera- tive capability and functional plasticity to generate conventional NKp46pos/CD56bright/CD16neg-low cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46neg-low/CD56dim/CD16neg 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, NKp46neg-low/CD56dim/CD16neg 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 unleash- ing natural killer cell alloreactivity early after haploidentical hematopoi- etic stem cell transplantation.
Introduction
The development over recent years of new protocols of allogeneic bone marrow transplant (BMT) arises from the need to rapidly identify a reliable source of hematopoietic stem cells (HSCs) to cure life-threatening hematologic malignan- cies. Indeed, the possibility of having a donor for nearly every patient requiring a
AR and CDV, EL and DM contributed equally to this work.
haematologica | 2018; 103(8)
ARTICLE