EBV-Associated Lymphoma Consortium Annual Meeting (Abstract)

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Submission Number: 6

Submission ID: 150781

Submission UUID: 038de749-a6fb-45be-9e21-4f14b388861b

Submission URI: /nci/ealv/venue/abstract

Submission Update: /nci/ealv/venue/abstract?token=Y83yvBOqk6jY7pz23Y8MJWQqv5iJmS5m57RxciPOLTo

Created: Wed, 09/03/2025 - 13:40

Completed: Wed, 09/03/2025 - 13:40

Changed: Wed, 09/03/2025 - 13:40

Remote IP address: 10.208.28.30

Submitted by: Anonymous

Language: English

Is draft: No

Webform: EBV-Associated Lymphoma Consortium Annual Meeting (Abstracts)

Submitted to: EBV-Associated Lymphoma Consortium Annual Meeting (Abstract)

OMB No.: 0925-0740
Expiration Date: 9/30/2025

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Epstein-Barr virus (EBV) is a human γ-herpesvirus that establishes latency and lifelong infection in B cells. Failure to control latent EBV infection can result in a variety of malignancies, including post-transplant lymphoproliferative disease (PTLD) in transplant recipients. Studies have implicated natural killer (NK) cells as critical in the host defense against EBV infection.

To understand the relationship of human NK cells and EBV in vivo, we utilized mass cytometry to analyze circulating NK cells in children that are seropositive  (n=11) or seronegative (n=6) for EBV. After gating on CD3-NKp46+ NK cells, clustering resulted in 10 distinct subpopulations. Higher proportions of NKG2A+ NK cell subsets were detected in the circulation of EBV-seropositive children as compared to seronegative children.

NKG2A recognizes non-classical HLA-E on target cells; we determined that HLA-E expression was markedly increased in EBV-infected cells compared to autologous uninfected B cells. To understand the NKG2A:HLA-E interactions in EBV-infected B cells, we generated HLA-E knockout (KO) EBV+ lymphoblastoid cell lines (LCL) using CRISPR/Cas9 gene editing and observed a significant increase (p <0.001) in killing of the KO EBV+ LCL by autologous and allogeneic NK cells as compared to wild-type EBV+ LCL or mock transfected EBV+ LCL. Moreover, increased killing of EBV+ LCL was also observed in the presence of anti-NKG2A as compared to untreated or isotype controls (p < 0.01).  EBV-responsive NK cells express high levels of the NKp30 and NKG2D activating receptors, and ligands that bind to NKG2D (MICA/MICB and ULBP) and NKp30 (B7-H6) are increased on EBV+LCL after coculture with NK cells. Disruption of the NKG2A:HLA-E immune checkpoint axis, either through the decrease of HLA-E on target cells or the more clinically relevant blocking of NKG2A on NK cells, enhances killing of EBV-infected B cells.