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Poorly cytotoxic terminally differentiated CD56CD16 NK cells accumulate in Kenyan children with Burkitt lymphomas


Forconi, Catherine S; Cosgrove, Cormac P; Saikumar-Lakshmi, Pryia; Nixon, Christina E; Foley, Joslyn; Ong'echa, John Michael; Otieno, Juliana A; Alter, Galit; Münz, Christian; Moormann, Ann M (2018). Poorly cytotoxic terminally differentiated CD56CD16 NK cells accumulate in Kenyan children with Burkitt lymphomas. Blood advances, 2(10):1101-1114.

Abstract

Natural killer (NK) cells are critical for restricting viral infections and mediating tumor immunosurveillance. Epstein-Barr virus (EBV) and malaria are known risk factors for endemic Burkitt lymphoma (eBL), the most common childhood cancer in equatorial Africa. To date, the composition and function of NK cells have not been evaluated in eBL etiology or pathogenesis. Therefore, using multiparameter flow cytometry and in vitro killing assays, we compared NK cells from healthy children and children diagnosed with eBL in Kenya. We defined 5 subsets based on CD56 and CD16 expression, including CD56CD16 We found that licensed and terminally differentiated perforin-expressing CD56CD16 NK cells accumulated in eBL children, particularly in those with high EBV loads (45.2%) compared with healthy children without (6.07%) or with (13.5%) malaria exposure ( = .0007 and .002, respectively). This progressive shift in NK cell proportions was concomitant with fewer CD56CD16 cells. Despite high MIP-1β expression, CD56CD16 NK cells had diminished cytotoxicity, with lower expression of activation markers NKp46, NKp30, and CD160 and the absence of TNF-α. Of note, the accumulation of poorly cytotoxic CD56CD16 NK cells resolved in long-term eBL survivors. Our study demonstrates impaired NK cell-mediated immunosurveillance in eBL patients but with the potential to restore a protective NK cell repertoire after cancer treatment. Characterizing NK cell dysfunction during coinfections with malaria and EBV has important implications for designing immunotherapies to improve outcomes for children diagnosed with eBL.

Abstract

Natural killer (NK) cells are critical for restricting viral infections and mediating tumor immunosurveillance. Epstein-Barr virus (EBV) and malaria are known risk factors for endemic Burkitt lymphoma (eBL), the most common childhood cancer in equatorial Africa. To date, the composition and function of NK cells have not been evaluated in eBL etiology or pathogenesis. Therefore, using multiparameter flow cytometry and in vitro killing assays, we compared NK cells from healthy children and children diagnosed with eBL in Kenya. We defined 5 subsets based on CD56 and CD16 expression, including CD56CD16 We found that licensed and terminally differentiated perforin-expressing CD56CD16 NK cells accumulated in eBL children, particularly in those with high EBV loads (45.2%) compared with healthy children without (6.07%) or with (13.5%) malaria exposure ( = .0007 and .002, respectively). This progressive shift in NK cell proportions was concomitant with fewer CD56CD16 cells. Despite high MIP-1β expression, CD56CD16 NK cells had diminished cytotoxicity, with lower expression of activation markers NKp46, NKp30, and CD160 and the absence of TNF-α. Of note, the accumulation of poorly cytotoxic CD56CD16 NK cells resolved in long-term eBL survivors. Our study demonstrates impaired NK cell-mediated immunosurveillance in eBL patients but with the potential to restore a protective NK cell repertoire after cancer treatment. Characterizing NK cell dysfunction during coinfections with malaria and EBV has important implications for designing immunotherapies to improve outcomes for children diagnosed with eBL.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Hematology
Language:English
Date:22 May 2018
Deposited On:26 Feb 2019 16:37
Last Modified:29 Jul 2020 09:44
Publisher:American Society of Hematology
ISSN:2473-9529
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1182/bloodadvances.2017015404
PubMed ID:29764843

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