Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients

Key Points iMC expand independent of the type of antitumor response and are not immunosuppressive in a cell-autonomous fashion iMC are licensed to become MDSC in vivo in the presence of GM-CSF

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Cellular immune suppression in cancer patients and its implication for dendritic cell therapy

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.3028 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 3028-3028 ◽

Cited By ~ 1

Author(s):

J. Nesselhut ◽

D. R. Lorenzen ◽

D. Marx ◽

R. Y. Chang ◽

C. Matthes ◽

...

Keyword(s):

Dendritic Cells ◽

Tumor Microenvironment ◽

Cancer Patients ◽

Immune Suppression ◽

Human Cancer ◽

Metronomic Chemotherapy ◽

Advanced Cancer Patients ◽

Down Regulation ◽

Antitumor Response ◽

Healthy Donors

3028 Background: The treatment of human cancer with monocyte-derived dendritic cells (MoDC) is a promising and innovative approach. However, many of the treated patients fail to respond to therapy. The reduced clinical antitumor response may be due to an inflammatory immune-suppressive tumor microenvironment. Regulatory T-cells (T-reg) and other cells with suppressive potential can promote an immune suppressive tumor microenvironment and thus play an important role in regulation of the immune response. Methods: Whole blood from n=100 cancer patients with various tumor types and from n=30 healthy donors were analysed by flow cytometry. CD4+ lymphocytes with immune suppressive potential were characterized by analysing the expression of CD25, CD39, CD127. Results: We found a significantly higher proportion of CD25+/CD39+ and of CD25+/CD127low T-helper cells in the blood of cancer patients as compared to healthy donors. This may indicate two different types of T-reg involved in immune suppression in cancer patients. Treatment of patients with metronomic chemotherapy induced a down-regulation of these cells. Interestingly, we found a subpopulation of cells within the lymphocyte gate characterized by CD2high and CD86 expression in cancer patients with very advanced stage, similar to such normally found in hemaphagocytic lymphohistiocytosis (HLH) patients characterized by exceeding high plasma concentration of IFN-g and IL-10 (Schneider et al. 2002). These cells can be down-regulated by treatment with a tetradecapeptide (Ezrin) known to act as an immune modulator with anti-viral activity leading to reduction of inflammatory cytokines. Conclusions: An efficient induction of a clinical antitumor response requires both a polarization of MoDC in a TH1 direction as well as changing an immune suppressive tumor microenvironment. For the first time, we identified HLH associated cells in advanced cancer patients. As HLH is characterized by hyperinflammation, these cells may indicate an inflammatory tumor microenvironment. Thus, anti-inflammatory therapy should be considered as co-treatment with immunotherapy with dendritic cells for down-regulation of immune suppressive cells (T-reg, CD2high/CD86+ cells) to promote a clinical antitumor response. No significant financial relationships to disclose.

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Targeting the glucose metabolism of monocytic myeloid-derived suppressor cells to stimulate cancer immunity.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.126 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 126-126

Author(s):

Jaspreet Singh Grewal ◽

Numan Al-Rayyan ◽

Jamaal Ritchie ◽

Paxton Schowe ◽

Cam Falkner ◽

...

Keyword(s):

T Cell ◽

Cancer Patients ◽

Transforming Growth Factor ◽

Phase 1 ◽

Suppressor Cells ◽

Simultaneous Increase ◽

Myeloid Derived Suppressor Cells ◽

Suppressive Activity ◽

Advanced Cancer Patients

126 Background: Myeloid derived suppressor cells (MDSCs) inhibit the expansion of tumor antigen-specific effector CD8+ T cells via different mechanisms including increased expression of arginase, transforming growth factor – β (TGF – β) and indoleamine 2,3-dioxygenase (IDO). Recently, MDSCs were found to over-express hypoxia inducible factor 1 alpha (HIF-1α) which is required for their differentiation. An essential transcriptional target of HIF-1α is 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) which synthesizes fructose 2,6-bisphosphate, an allosteric stimulator of glycolysis and of proliferation via stimulation of cyclin dependent kinase-1 (CDK1). We hypothesized that MDSCs might over-express PFKFB3 which in turn might be required for their function as T cell suppressors. Methods: We used monocytic MDSCs (M-MDSCs) induced by co-culture with A375 melanoma cells, M-MDSCs from metastatic melanoma patients, murine bone marrow MDSCs and splenic M-MDSCs from B16 F10 tumor bearing mice for our studies. T cell suppression assays were performed to analyze M-MDSC suppression and reversal following PFKFB3 blockade. Results: We found that M-MDSCs have increased PFKFB3 expression. We also found that PFK-158 administration in B16 (wild-type) melanoma-bearing mice results in a marked reduction in MDSCs and a simultaneous increase in CD8+ T cell infiltration in the tumors. We analyzed three advanced cancer patients for circulating MDSCs before and after PFK-158 administration as part of a multi-center phase 1 clinical trial. And, we found that the MDSCs were markedly reduced in each patient. In addition, we have generated data for MDSC suppressive activity following in vitro treatment with PFK-158 showing reversal of suppressive activity. Conclusions: Taken together, these data indicate that selective inhibition of PFKFB3 may be a novel approach to target MDSCs and combinations of PFKFB3 inhibitors with immunotherapies may be a rational strategy to promote durable immune-mediated remissions in cancer patients.

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Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer

The Journal of Immunology ◽

10.4049/jimmunol.166.1.678 ◽

2001 ◽

Vol 166 (1) ◽

pp. 678-689 ◽

Cited By ~ 885

Author(s):

Bond Almand ◽

Joseph I. Clark ◽

Ekaterina Nikitina ◽

James van Beynen ◽

Nicholas R. English ◽

...

Keyword(s):

Cancer Patients ◽

Myeloid Cells ◽

Immature Myeloid Cells

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Induction of an antitumor response using dendritic cells transfected with DNA constructs encoding the HLA-A*02:01-restricted epitopes of tumor-associated antigens in culture of mononuclear cells of breast cancer patients

Immunologic Research ◽

10.1007/s12026-015-8735-0 ◽

2015 ◽

Vol 64 (1) ◽

pp. 171-180 ◽

Cited By ~ 3

Author(s):

Sergey Vital’evich Sennikov ◽

Julia Alexandrovna Shevchenko ◽

Vasilii Vasil’evich Kurilin ◽

Julia Nikolaevna Khantakova ◽

Julia Anatol’evna Lopatnikova ◽

...

Keyword(s):

Breast Cancer ◽

Dendritic Cells ◽

Cancer Patients ◽

Mononuclear Cells ◽

Breast Cancer Patients ◽

Antitumor Response ◽

Tumor Associated Antigens

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Functional Characterictics of Bone Marrow Immune Suppressive Cells in Patients with Gastric Cancer

International Journal of Immunopathology and Pharmacology ◽

10.1177/039463209801100307 ◽

1998 ◽

Vol 11 (3) ◽

pp. 171-178 ◽

Cited By ~ 1

Author(s):

S. A. Kusmartsev ◽

I. N. Kusmartseva ◽

N.V. Tcherdyntseva ◽

S.G. Afanasyev ◽

N.V. Vasilyev

Keyword(s):

Gastric Cancer ◽

Bone Marrow ◽

Cancer Patients ◽

Nk Cell ◽

Killer Cell ◽

Cell Activity ◽

Adherent Cell ◽

Target Cells ◽

Suppressive Activity ◽

Normal Peripheral Blood

The progressive growth of cancer is accompanied by alteration in the regulation of both hematopoiesis and immunity. In this study we assessed the immunoregulatory features of bone marrow (BM) plastic non-adherent cells in patients with primary gastric cancer. Suppressive activity of BM cells or its culture supernatants was determined by inhibition of normal peripheral blood mononuclear cells (PBMC) response to phytohemagglutinin (PHA) or NK cell cytotoxicity. It was shown that fresh isolated BM cells from gastric cancer patients are capable markedly inhibit the mitogen-induced proliferative response of PBMC as well as NK cell cytotoxic activity. The immune suppressive cell activity was revealed among the non-adherent cell fraction only. The addition of indomethacin, inhibitor of prostaglandin synthesis, or NG-monomethyl-L-arginine (L-NMA), a competitive inhibitor of nitric oxide (NO) synthase, to the cultures did not diminish the suppressive effect of non-adherent BM cells in cancer patients. This BM cell mediated suppression of mitogen-induced proliferation of PBMC could be reduced, at least in part, by addition of neutralizing monoclonal antibodies to TGF-β. When normal PBMC were cultured with supernatant of BM cells derived from cancer patients, their natural killer cell activity was strongly down-regulated. It was shown also that NK cell capacity to bind tumor target cells was reduced in the presence of BM cell supernatant. Taken together our data demonstrate that BM non-adherent cell of patients with gastric cancer exhibit the immune suppressive activity which should be supposed to contribute to impairment of tumor immunity as malignant growth progresses.

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