RNA-Seq Analysis Reveals CCR5 as a Key Target for CRISPR Gene Editing to Regulate In Vivo NK Cell Trafficking.

Autor: Levy ER; National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.; The Department of Molecular Medicine, George Washington University, Washington, DC 20052, USA., Clara JA; National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA., Reger RN; National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA., Allan DSJ; National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA., Childs RW; National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20814, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2021 Feb 19; Vol. 13 (4). Date of Electronic Publication: 2021 Feb 19.
DOI: 10.3390/cancers13040872
Abstrakt: A growing number of natural killer (NK) cell-based immunotherapy trials utilize ex vivo expansion to grow and activate allogenic and autologous NK cells prior to administration to patients with malignancies. Recent data in both murine and macaque models have shown that adoptively infused ex vivo expanded NK cells have extensive trafficking into liver tissue, with relatively low levels of homing to other sites where tumors often reside, such as the bone marrow or lymph nodes. Here, we evaluated gene and surface expression of molecules involved in cellular chemotaxis in freshly isolated human NK cells compared with NK cells expanded ex vivo using two different feeder cells lines: Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) or K562 cells with membrane-bound (mb) 4-1BB ligand and interleukin (IL)-21. Expanded NK cells had altered expression in a number of genes that encode chemotactic ligands and chemotactic receptors that impact chemoattraction and chemotaxis. Most notably, we observed drastic downregulation of C-X-C chemokine receptor type 4 (CXCR4) and upregulation of C-C chemokine receptor type 5 (CCR5) transcription and phenotypic expression. clustered regularly interspaced short palindromic repeats (CRISPR) gene editing of CCR5 in expanded NK cells reduced cell trafficking into liver tissue and increased NK cell presence in the circulation following infusion into immunodeficient mice. The findings reported here show that ex vivo expansion alters multiple factors that govern NK cell homing and define a novel approach using CRISPR gene editing that reduces sequestration of NK cells by the liver.
Databáze: MEDLINE
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