Advertisement

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 and Gerritje J.W. van der Windt

Key Points

  • CD8+ T cells from CLL patients display aberrations in mitochondrial and glucose metabolism prior to and after stimulation.

  • CD8+ CD19-CAR T cells have enhanced mitochondrial biogenesis in complete responding CLL patients correlating with expansion and persistence.

Abstract

In chronic lymphocytic leukemia (CLL), acquired T cell dysfunction impedes development of effective immunotherapeutic strategies, through 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 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 PGC-1α, 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 (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 to non-responders, 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. Please note: the May 10, 2019 Blood First Edition publication of this paper included an incorrect version of the abstract. The correct abstract appears above.

  • Submitted November 14, 2018.
  • Revision received April 23, 2019.
  • Accepted April 20, 2019.