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 - 2019

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
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. / Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy. In: Blood. 2019 ; Vol. 134, No. 1. pp. 44-58.
@article{3a0bc71f99c149c88556e5db95900260,
title = "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 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.",
author = "{van Bruggen}, {Jaco A. C.} and Martens, {Anne W. J.} and Fraietta, {Joseph A.} and Tom Hofland and Tonino, {Sanne H.} and Eric Eldering and Mark-David Levin and Siska, {Peter J.} and Sanne Endstra 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.}",
year = "2019",
doi = "10.1182/blood.2018885863",
language = "English",
volume = "134",
pages = "44--58",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "1",

}

van Bruggen, JAC, Martens, AWJ, Fraietta, JA, Hofland, T, Tonino, SH, Eldering, E, Levin, M-D, Siska, PJ, Endstra, S, Rathmell, JC, June, CH, Porter, DL, Melenhorst, JJ, Kater, AP & van der Windt, GJW 2019, 'Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy' Blood, vol. 134, no. 1, pp. 44-58. https://doi.org/10.1182/blood.2018885863

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

In: Blood, Vol. 134, No. 1, 2019, p. 44-58.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy

AU - van Bruggen, Jaco A. C.

AU - Martens, Anne W. J.

AU - Fraietta, Joseph A.

AU - Hofland, Tom

AU - Tonino, Sanne H.

AU - Eldering, Eric

AU - Levin, Mark-David

AU - Siska, Peter J.

AU - Endstra, Sanne

AU - Rathmell, Jeffrey C.

AU - June, Carl H.

AU - Porter, David L.

AU - Melenhorst, J. Joseph

AU - Kater, Arnon P.

AU - van der Windt, Gerritje J. W.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85069272964&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31076448

U2 - 10.1182/blood.2018885863

DO - 10.1182/blood.2018885863

M3 - Article

VL - 134

SP - 44

EP - 58

JO - Blood

JF - Blood

SN - 0006-4971

IS - 1

ER -

van Bruggen JAC, Martens AWJ, Fraietta JA, Hofland T, Tonino SH, Eldering E et al. Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+ T cells and impede CAR T-cell efficacy. Blood. 2019;134(1):44-58. https://doi.org/10.1182/blood.2018885863