| Autor: |
van Bruggen, Jaco A.C., Martens, Anne W.J., Fraietta, Joseph A., Hofland, Tom, Tonino, Sanne H., Eldering, Eric, Levin, Mark-David, Siska, Peter J., Endstra, Sanne, Rathmell, Jeffrey C., June, Carl H., Porter, David L., Melenhorst, J. Joseph, Kater, Arnon P., van der Windt, Gerritje J.W. |
| Zdroj: |
Blood; July 2019, Vol. 134 Issue: 1 p44-58, 15p |
| Abstrakt: |
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 γ coactivator 1-α, 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. |
| Databáze: |
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