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Hypoxia Selectively Impairs CAR-T Cells In Vitro

1
ProMab Biotechnologies, 2600 Hilltop Drive, Richmond, CA 94806, USA
2
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; https://doi.org/10.3390/cancers11050602
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)
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Abstract

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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