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 ...
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 gamma coactivator 1-alpha, 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.
; 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. 
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