Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells

• Type of Material: Article
• Authors: Evelyn O. Ojo, Case Western Reserve University; Ashish Sharma, Emory University; Ruifu Liu, Case Western Reserve University; Stephen Moreton, Case Western Reserve University; Mary-Ann Checkley-Luttge, Case Western Reserve University; Kalpana Gupta, Case Western Reserve University; Grace Lee, Case Western Reserve University; Dean A. Lee, Nationwide Children's Hospital; Folashade Otegbeye, University Hospitals of Cleveland; Rafick-Pierre Sekaly, Emory University; Marcos de Lima, University Hospitals of Cleveland; David N. Wald, Case Western Reserve University
• Language: English
• Date: 2019-10-17
• Publisher: NATURE PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2019
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-019-51287-6
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 9
• Issue: 1
• Start Page: 14916
• End Page: 14916
• Grant/Funding Information: This study was supported by NIH T32 GM007250 (E.O.) and the Leukemia and Lymphoma Society TRP-6500-16 (DNW). This research was supported by the Cytometry and Microscopy, Hematopoietic Biorepository and Cellular Therapy, and Imaging Research cores from the Shared Resource of the Case Comprehensive Cancer Center (P30 CA043703). The authors thank Grace Lee for assistance in NK cell isolation.
• Keywords: PROLIFERATION; ALLOREACTIVITY; RECEPTORS; VIVO EXPANSION; NATURAL-KILLER-CELLS; Science & Technology; CANCER; IMMUNOTHERAPY; Science & Technology - Other Topics; Multidisciplinary Sciences; THERAPY
• Research Categories: Biology, Cell; Health Sciences, Oncology

Abstract

NK cell adoptive therapy is a promising cancer therapeutic approach, but there are significant challenges that limiting its feasibility and clinical efficacy. One difficulty is the paucity of clinical grade manufacturing platforms to support the large scale expansion of highly active NK cells. We created an NK cell feeder cell line termed ‘NKF’ through overexpressing membrane bound IL-21 that is capable of inducing robust and sustained proliferation (>10,000-fold expansion at 5 weeks) of highly cytotoxic NK cells. The expanded NK cells exhibit increased cytotoxic function against a panel of blood cancer and solid tumor cells as compared to IL-2-activated non-expanded NK cells. The NKF-expanded NK cells also demonstrate efficacy in mouse models of human sarcoma and T cell leukemia. Mechanistic studies revealed that membrane-bound IL-21 leads to an activation of a STAT3/c-Myc pathway and increased NK cell metabolism with a shift towards aerobic glycolysis. The NKF feeder cell line is a promising new platform that enables the large scale proliferation of highly active NK cells in support of large scale third party NK cell clinical studies that have been recently intiatied. These results also provide mechanistic insights into how membrane-bound IL-21 regulates NK cell expansion.