Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy

Jaco A. C. van Bruggen, Anne W. J. Martens, Joseph A. Fraietta, Tom Hofland, Sanne H. Tonino, Eric Eldering, Mark-David Levin, Peter J. Siska, Sanne Endstra, Jeffrey C. Rathmell, Carl H. June, David L. Porter, J. Joseph Melenhorst, Arnon P. Kater, Gerritje J. W. van der Windt

Research output: Contribution to journalArticleAcademicpeer-review

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 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 andmitochondrial fitness of CD8+ T cells are impaired in CLL. Therefore, boostingmitochondrial biogenesis in CAR T cells might improve the efficacy of CAR T-cell therapy and other emerging cellular immunotherapies.
Original languageEnglish
Pages (from-to)44-58
JournalBlood
Volume134
Issue number1
DOIs
Publication statusPublished - 4 Jul 2019
Externally publishedYes

Cite this

van Bruggen, J. A. C., Martens, A. W. J., Fraietta, J. A., Hofland, T., Tonino, S. H., Eldering, E., ... van der Windt, G. J. W. (2019). Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy. Blood, 134(1), 44-58. https://doi.org/10.1182/blood.2018885863