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3. Functional Differences Between EBV- and CMV-Specific CD8+ T cells Demonstrate Heterogeneity of T cell Dysfunction in CLL

Author

Hofland, Tom, primary, de Weerdt, Iris, additional, Endstra, Sanne, additional, Jongejan, Aldo, additional, Platenkamp, Laura, additional, Remmerswaal, Ester B.M., additional, Moerland, Perry D., additional, ten Berge, Ineke J.M., additional, Levin, Mark-David, additional, Kater, Arnon P., additional, and Tonino, Sanne H., additional

Published
2020
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4. Natural Killer Cell Hypo-responsiveness in Chronic Lymphocytic Leukemia can be Circumvented In Vitro by Adequate Activating Signaling

Author

Hofland, Tom, primary, Endstra, Sanne, additional, Gomes, Calum K.P., additional, de Boer, Renate, additional, de Weerdt, Iris, additional, Bobkov, Vladimir, additional, Riedl, Jurgen A., additional, Heukers, Raimond, additional, Smit, Martine J., additional, Eldering, Eric, additional, Levin, Mark-David, additional, Kater, Arnon P., additional, and Tonino, Sanne H., additional

Published
2019
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5. Chronic Lymphocytic Leukemia Cells Impair Mitochondrial Fitness in CD8+ T Cells and Impede CAR T Cell Efficacy

Author

Van Bruggen, Jaco A. C., primary, Martens, Anne W. J., additional, Fraietta, Joseph A, additional, Hofland, Tom, additional, Tonino, Sanne, additional, Eldering, Eric, additional, Levin, Mark-David, additional, Siska, Peter J., additional, Endstra, Sanne, additional, Rathmell, Jeffrey C, additional, June, Carl H, additional, Porter, David L., additional, Melenhorst, J. Joseph, additional, van der Windt, Gerritje J. W., additional, and Kater, Arnon P., additional

Published
2018
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8. Chronic lymphocytic leukemia cells impair mitochondrial fitness in CD8+T cells and impede CAR T-cell efficacy

Author

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., and van der Windt, Gerritje J.W.

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.

Published
2019
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10. Functional Differences Between EBV- and CMV-Specific CD8 + T cells Demonstrate Heterogeneity of T cell Dysfunction in CLL.

Author

Hofland T, de Weerdt I, Endstra S, Jongejan A, Platenkamp L, Remmerswaal EBM, Moerland PD, Ten Berge IJM, Levin MD, Kater AP, and Tonino SH

Abstract

Acquired T cell dysfunction is a hallmark of chronic lymphocytic leukemia (CLL), and is linked to an increased risk of infections, but also reduced immune surveillance and disappointing responses to autologous T cell-based immunotherapy. The mechanisms of T cell dysfunction in CLL are not well understood. Studying immunity against chronic viruses allows for detailed analysis of the effect of CLL on T cells chronically exposed to a specific antigen. Cytomegalovirus (CMV) reactivations are rare in CLL, which corroborates with preserved CMV-specific T cell function. Epstein-Barr virus (EBV) is another herpesvirus that results in chronic infection, but unlike CMV, is characterized by subclinical reactivations in CLL patients. Since both herpesviruses induce strong CD8 + T cell responses, but have different clinical outcomes, studying these specific T cells may shed light on the mechanisms of CLL-induced T cell dysfunction. We first analyzed the phenotype of EBV-specific CD8 + T cells in CLL and healthy controls, and found that in CLL EBV-specific CD8 + T cells are in an advanced differentiation state with higher expression of inhibitory receptors. Secondly, CLL-derived EBV-specific CD8 + T cells show reduced cytotoxic potential, in contrast to CMV-specific T cells. Finally, we performed transcriptome analysis to visualize differential modulation by CLL of these T cell subsets. While T cell activation and differentiation genes are unaffected, in EBV-specific T cells expression of genes involved in synapse formation and T cell exhaustion is altered. Our findings on the heterogeneity of antigen specific T cell function in CLL aids in understanding immune-dysregulation in this disease., (Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Published
2020
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