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

Blood. 2019 Jul 4;134(1):44-58. doi: 10.1182/blood.2018885863. Epub 2019 May 10.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunotherapy, Adoptive*
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy
  • Male
  • Middle Aged
  • Mitochondria / metabolism*
  • Organelle Biogenesis
  • Receptors, Chimeric Antigen

Substances

  • Receptors, Chimeric Antigen

Associated data

  • ClinicalTrials.gov/NCT01747486
  • ClinicalTrials.gov/NCT01029366