van Bruggen, Jaco A. C. and Martens, Anne W. J. and Fraietta, Joseph A. and Hofland, Tom and Tonino, Sanne H. and Eldering, Eric and Levin, Mark-David and Siska, Peter J. and Endstra, Sanne and Rathmell, Jeffrey C. and June, Carl H. and Porter, David L. and Melenhorst, J. Joseph and Kater, Arnon P. and van der Windt, Gerritje J. W. (2019) Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8(+) T cells and impede CAR T-cell efficacy. BLOOD, 134 (1). pp. 44-58. ISSN 0006-4971, 1528-0020
Full text not available from this repository. (Request a copy)Abstract
In chronic lymphocytic leukemia (CLL), acquired T-cell dysfunction impedes development of effective immunotherapeutic strategies, through as-yet unresolved mechanisms. We have previously shown that CD8(+) T cells in CLL exhibit impaired activation and reduced glucose uptake after stimulation. CD8(+) T cells in CLL patients are chronically exposed to leukemic B cells, which potentially impacts metabolic homeostasis resulting in aberrant metabolic reprogramming upon stimulation. Here, we report that resting CD8(+) T cells in CLL have reduced intracellular glucose transporter 1 (GLUT1) reserves, and have an altered mitochondrial metabolic profile as displayed by increased mitochondrial respiration, membrane potential, and levels of reactive oxygen species. This coincided with decreased levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, and in line with that, CLL-derived CD8(+) T cells showed impaired mitochondrial biogenesis upon stimulation. In search of a therapeutic correlate of these findings, we analyzed mitochondrial biogenesis in CD19-directed chimeric antigen receptor (CAR) CD8(+) T cells prior to infusion in CLL patients (who were enrolled in NCT01747486 and NCT01029366 [https://clinicaltrials.gov]). Interestingly, in cases with a subsequent complete response, the infused CD8(+) CAR T cells had increased mitochondrial mass compared with nonresponders, which positively correlated with the expansion and persistence of CAR T cells. Our findings demonstrate that GLUT1 reserves and mitochondrial fitness of CD8(+) T cells are impaired in CLL. Therefore, boosting mitochondrial biogenesis in CAR T cells might improve the efficacy of CAR T-cell therapy and other emerging cellular immunotherapies.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | B-CELLS; METABOLISM; CLL; REMISSIONS; CAPACITY; FATE; IMMUNODEFICIENCY; TRANSPLANTATION; INTERLEUKIN-10; SUPPRESSION; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 07 Apr 2020 08:39 |
| Last Modified: | 07 Apr 2020 08:39 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26655 |
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