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

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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 establishes 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 those 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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