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Immunotherapy

The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia

Leukemia volume 31, pages 470–478 (2017)Cite this article

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Abstract

Immune dysfunctions in chronic lymphocytic leukemia (CLL) contribute to tumor immune escape and attenuate immune-based therapies. Monocytes/macrophages represent key components of cancer immune surveillance and effectors for antibody-mediated antitumor effects. Monocytes display an altered subset composition in CLL. Moreover, we find a changed metabolic phenotype: glucose uptake, glucose transporters and expression of glycolytic molecules are reduced. Our data establish a link between glycolytic competence and monocyte-mediated phagocytosis of tumor cells. Furthermore, we report that CLL monocytes express Bruton’s tyrosine kinase (BTK). Our observations suggest that using BTK inhibitors in CLL might further aggravate the observed immune metabolic defects in monocytes. Triggering the programmed cell death-1 (PD-1) checkpoint on monocytes hampers glycolysis, phagocytosis and BTK signaling. Conversely, disrupting PD-1/PD-L1 signaling reverses these immune metabolic dysfunctions. Taken together, our findings imply a novel metabolic interplay between CLL cells and monocytes and that blocking PD-1/PD-L1 might restore metabolic together with antitumor activity of CLL monocytes/macrophages.

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Acknowledgements

We acknowledge the kind assistance of the Core Unit Cell Sorting and Immunomonitoring Erlangen. DM was supported by the IZKF Erlangen, the European Hematology Association (EHA) and the José Carreras Leukemia Foundation. MQ was supported by the IZKF Erlangen. RJ was supported by the ELAN program of the University of Erlangen-Nuremberg. LW was supported by the i-Target program of the Elitenetzwerk Bayern.

Author contributions

MQ, HB, MB and LW performed research and analyzed data. AM and RJ helped designing the study and writing the manuscript. DM designed the study, analyzed data and wrote the manuscript.

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  1. Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany

    M Qorraj, H Bruns, M Böttcher, L Weigand, D Saul, A Mackensen, R Jitschin & D Mougiakakos

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  1. M Qorraj
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  2. H Bruns
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Correspondence to D Mougiakakos.

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Qorraj, M., Bruns, H., Böttcher, M. et al. The PD-1/PD-L1 axis contributes to immune metabolic dysfunctions of monocytes in chronic lymphocytic leukemia. Leukemia 31, 470–478 (2017). https://doi.org/10.1038/leu.2016.214

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