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

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 ? coactivator 1-?, 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.

SUBMITTER: van Bruggen JAC

PROVIDER: S-EPMC7022375 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

van Bruggen Jaco A C JAC Martens Anne W J AWJ Fraietta Joseph A JA Hofland Tom T Tonino Sanne H SH Eldering Eric E Levin Mark-David MD Siska Peter J PJ Endstra Sanne S Rathmell Jeffrey C JC June Carl H CH Porter David L DL Melenhorst J Joseph JJ Kater Arnon P AP van der Windt Gerritje J W GJW

Blood 20190510 1

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. ...[more]

PMID: 31076448

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

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Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8<sup>+</sup> T cells and impede CAR T-cell efficacy.

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

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Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8&lt;sup&gt;+&lt;/sup&gt; T cells and impede CAR T-cell efficacy.

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Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8<sup>+</sup> T cells and impede CAR T-cell efficacy.