Regina Jitschin

Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation.

Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that can expand in response to inflammatory signals. Predominantly studied in cancer, MDSCs suppress T cells utilizing various mechanisms. In allogeneic hematopoietic stem cell transplantation (allo-HSCT) therapy-related toxicity and alloreactivity increase inflammatory cytokines that might favor an MDSC accumulation. To address this question, circulating CD14+HLA-DRlow/neg cells were studied retrospectively in 51 allo-HSCT patients. These cells represent one of the few well-described human MDSC subsets under physiological and pathological conditions. The frequency of CD14+HLA-DRlow/neg cells was significantly increased after allo-HSCT, especially in patients with acute graft-versus-host disease. Compared to healthy donor cells they were pSTAT1low (phosphorylated signal transducer and activator of transcription) and indoleamine 2,3-dioxygenase (IDO)high. Serum levels of granulocyte colony-stimulating factor and interleukin-6, which both have been linked to MDSC induction, correlated positively with the frequency of CD14+HLA-DRlow/neg cells. In vitro dysfunction of patient T cells, such as reduced proliferative capacity or CD3ζ-chain expression, was rescued by blocking the IDO activity of CD14+HLA-DRlow/neg cells. Overall, we identified a T-cell-suppressive monocytic population that expands after allo-HSCT. The mechanisms responsible for such accumulation remain to be elucidated. It will be of great interest to prospectively investigate the influence of these cells on the graft-versus-tumor and -host reaction.

Mitochondrial metabolism contributes to oxidative stress and reveals therapeutic targets in chronic lymphocytic leukemia

Alterations of cellular metabolism represent a hallmark of cancer. Numerous metabolic changes are required for malignant transformation, and they render malignant cells more prone to disturbances in the metabolic framework. Despite the high incidence of chronic lymphocytic leukemia (CLL), metabolism of CLL cells remains a relatively unexplored area. The examined untreated CLL patients displayed a metabolic condition known as oxidative stress, which was linked to alterations in their lymphoid compartment. Our studies identified mitochondrial metabolism as the key source for abundant reactive oxygen species (ROS). Unlike in other malignant cells, we found increased oxidative phosphorylation in CLL cells but not increased aerobic glycolysis. Furthermore, CLL cells adapted to intrinsic oxidative stress by upregulating the stress-responsive heme-oxygenase-1 (HO-1). Our data implicate that HO-1 was, beyond its function as an antioxidant, involved in promoting mitochondrial biogenesis. Thus ROS, adaptation to ROS, and mitochondrial biogenesis appear to form a self-amplifying feedback loop in CLL cells. Taking advantage of the altered metabolic profile, we were able to selectively target CLL cells by PK11195. This benzodiazepine derivate blocks the mitochondrial F1F0-ATPase, leads to a surplus production of mitochondrial superoxide, and thereby induces cell death in CLL cells. Taken together, our findings depict how bioenergetics and redox characteristics could be therapeutically exploited in CLL.

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

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.

Contact-Dependent Depletion of Hydrogen Peroxide by Catalase Is a Novel Mechanism of Myeloid-Derived Suppressor Cell Induction Operating in Human Hepatic Stellate Cells

Myeloid-derived suppressor cells (MDSC) represent a unique cell population with distinct immunosuppressive properties that have been demonstrated to shape the outcome of malignant diseases. Recently, human hepatic stellate cells (HSC) have been reported to induce monocytic-MDSC from mature CD14+ monocytes in a contact-dependent manner. We now report a novel and unexpected mechanism by which CD14+HLADRlow/− suppressive cells are induced by catalase-mediated depletion of hydrogen peroxide (H2O2). Incubation of CD14+ monocytes with catalase led to a significant induction of functional MDSC compared with media alone, and H2O2 levels inversely correlated with MDSC frequency (r = −0.6555, p < 0.05). Catalase was detected in primary HSC and a stromal cell line, and addition of the competitive catalase inhibitor hydroxylamine resulted in a dose-dependent impairment of MDSC induction and concomitant increase of H2O2 levels. The NADPH-oxidase subunit gp91 was significantly increased in catalase-induced MDSC as determined by quantitative PCR outlining the importance of oxidative burst for the induction of MDSC. These findings represent a so far unrecognized link between immunosuppression by MDSC and metabolism. Moreover, this mechanism potentially explains how stromal cells can induce a favorable immunological microenvironment in the context of tissue oxidative stress such as occurs during cancer therapy.

CXCL12 promotes glycolytic reprogramming in acute myeloid leukemia cells via the CXCR4/mTOR axis

CXCL12 promotes glycolytic reprogramming in acute myeloid leukemia cells via the CXCR4/mTOR axis

CLL-cell-mediated MDSC induction by exosomal miR-155 transfer is disrupted by vitamin D.

Abstract Leukemia accepted article preview online, 23 December 2016. doi:10.1038/leu.2016.378.

Phenotypic and functional alterations of myeloid-derived suppressor cells during the disease course of multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system involving dysregulated encephalitogenic T cells. Myeloid‐derived suppressor cells (MDSCs) have been recognized for their important function in regulating T‐cell responses. Recent studies have indicated a role for MDSCs in autoimmune diseases, but their significance in MS is not clear. Here, we assessed the frequencies of CD14+HLA‐DRlow monocytic MDSCs (Mo‐MDSCs) and CD33+CD15+CD11b+HLA‐DRlow granulocytic MDSCs (Gr‐MDSCs) and investigated phenotypic and functional differences of Mo‐MDSCs at different clinical stages of MS and in healthy subjects (HC). Increased frequencies of Mo‐MDSCs (P < 0.05) and Gr‐MDSCs (P < 0.05) were observed in relapsing‐remitting MS patients during relapse (RRMS‐relapse) compared to stable RRMS (RRMS‐rem). Secondary progressive MS (SPMS) patients displayed a decreased frequency of Mo‐MDSCs and Gr‐MDSCs compared to HC (P < 0.05). Mo‐MDSCs within RRMS patients expressed significantly higher cell surface protein levels of CD86 and CD163 compared to SPMS patients. Mo‐MDSCs within SPMS exhibited decreased mRNA expression of interleukin‐10 and heme oxygenase 1 compared to RRMS and HC. Analysis of T‐cell regulatory function of Mo‐MDSCs demonstrated T‐cell suppressive capacity in RRMS and HCs, while Mo‐MDSCs of SPMS promoted autologous T‐cell proliferation, which aligned with a differential cytokine profile compared to RRMS and HCs. This study is the first to show phenotypic and functional shifts of MDSCs between clinical stages of MS, suggesting a role for MDSCs as a therapeutic target to prevent MS disease progression.