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

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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 []). 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
Issue number1
Publication statusPublished - 4 Jul 2019
Externally publishedYes

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