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Open AccessArticle

Hypoxia Selectively Impairs CAR-T Cells In Vitro

ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA
Department of Medicine, University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73104, USA
Authors to whom correspondence should be addressed.
Cancers 2019, 11(5), 602;
Received: 4 March 2019 / Revised: 18 April 2019 / Accepted: 26 April 2019 / Published: 30 April 2019
(This article belongs to the Special Issue Immunotherapy, Tumor Microenvironment and Survival Signaling)
Hypoxia is a major characteristic of the solid tumor microenvironment. To understand how chimeric antigen receptor-T cells (CAR-T cells) function in hypoxic conditions, we characterized CD19-specific and BCMA-specific human CAR-T cells generated in atmospheric (18% oxygen) and hypoxic (1% oxygen) culture for expansion, differentiation status, and CD4:CD8 ratio. CAR-T cells expanded to a much lower extent in 1% oxygen than in 18% oxygen. Hypoxic CAR-T cells also had a less differentiated phenotype and a higher CD4:CD8 ratio than atmospheric CAR-T cells. CAR-T cells were then added to antigen-positive and antigen-negative tumor cell lines at the same or lower oxygen level and characterized for cytotoxicity, cytokine and granzyme B secretion, and PD-1 upregulation. Atmospheric and hypoxic CAR-T cells exhibited comparable cytolytic activity and PD-1 upregulation; however, cytokine production and granzyme B release were greatly decreased in 1% oxygen, even when the CAR-T cells were generated in atmospheric culture. Together, these data show that at solid tumor oxygen levels, CAR-T cells are impaired in expansion, differentiation and cytokine production. These effects may contribute to the inability of CAR-T cells to eradicate solid tumors seen in many patients. View Full-Text
Keywords: CAR-T; hypoxia; tumor; microenvironment; CD19; BCMA; immunotherapy CAR-T; hypoxia; tumor; microenvironment; CD19; BCMA; immunotherapy
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Berahovich, R.; Liu, X.; Zhou, H.; Tsadik, E.; Xu, S.; Golubovskaya, V.; Wu, L. Hypoxia Selectively Impairs CAR-T Cells In Vitro. Cancers 2019, 11, 602.

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