Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

Myeloid-derived suppressor cells (MDSCs) are a group of immunosuppressive cells that play crucial roles in promoting tumor growth and protecting tumors from immune recognition in tumor-bearing mice and cancer patients. Recently, it has been shown that the metabolic activity of MDSCs plays an important role in the regulation of their inhibitory function, especially in the processes of tumor occurrence and development. The MDSC metabolism, such as glycolysis, fatty acid oxidation and amino acid metabolism, is rewired in the tumor microenvironment (TME), which enhances the immunosuppressive activity, resulting in effector T cell apoptosis and suppressive cell proliferation. Herein, we summarized the recent progress in the metabolic reprogramming and immunosuppressive function of MDSCs during tumorigenesis.

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Myeloid-derived suppressor cell function and epigenetic expression evolves over time after surgical sepsis

Critical Care ◽

10.1186/s13054-019-2628-x ◽

2019 ◽

Vol 23 (1) ◽

Cited By ~ 14

Author(s):

McKenzie K. Hollen ◽

Julie A. Stortz ◽

Dijoia Darden ◽

Marvin L. Dirain ◽

Dina C. Nacionales ◽

...

Keyword(s):

Cell Function ◽

Expression Patterns ◽

Suppressor Cells ◽

Myeloid Cell ◽

Suppressor Cell ◽

Myeloid Derived Suppressor Cell ◽

T Lymphocyte Proliferation ◽

Suppressive Phenotype ◽

Sepsis Survivors ◽

Over Time

Abstract Background Sepsis is an increasingly significant challenge throughout the world as one of the major causes of patient morbidity and mortality. Central to the host immunologic response to sepsis is the increase in circulating myeloid-derived suppressor cells (MDSCs), which have been demonstrated to be present and independently associated with poor long-term clinical outcomes. MDSCs are plastic cells and potentially modifiable, particularly through epigenetic interventions. The objective of this study was to determine how the suppressive phenotype of MDSCs evolves after sepsis in surgical ICU patients, as well as to identify epigenetic differences in MDSCs that may explain these changes. Methods Circulating MDSCs from 267 survivors of surgical sepsis were phenotyped at various intervals over 6 weeks, and highly enriched MDSCs from 23 of these samples were co-cultured with CD3/CD28-stimulated autologous T cells. microRNA expression from enriched MDSCs was also identified. Results We observed that MDSC numbers remain significantly elevated in hospitalized sepsis survivors for at least 6 weeks after their infection. However, only MDSCs obtained at and beyond 14 days post-sepsis significantly suppressed T lymphocyte proliferation and IL-2 production. These same MDSCs displayed unique epigenetic (miRNA) expression patterns compared to earlier time points. Conclusions We conclude that in sepsis survivors, immature myeloid cell numbers are increased but the immune suppressive function specific to MDSCs develops over time, and this is associated with a specific epigenome. These findings may explain the chronic and persistent immune suppression seen in these subjects.

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Myeloid-derived suppressor cell subtypes differentially influence T-cell function, T-helper subset differentiation, and clinical course in CLL

Leukemia ◽

10.1038/s41375-021-01249-7 ◽

2021 ◽

Author(s):

Gerardo Ferrer ◽

Byeongho Jung ◽

Pui Yan Chiu ◽

Rukhsana Aslam ◽

Florencia Palacios ◽

...

Keyword(s):

T Cell ◽

Cell Function ◽

Clinical Course ◽

Suppressor Cells ◽

Suppressor Cell ◽

Cancer Pathogenesis ◽

Myeloid Derived Suppressor Cell ◽

And Function

AbstractCancer pathogenesis involves the interplay of tumor- and microenvironment-derived stimuli. Here we focused on the influence of an immunomodulatory cell type, myeloid-derived suppressor cells (MDSCs), and their lineage-related subtypes on autologous T lymphocytes. Although MDSCs as a group correlated with an immunosuppressive Th repertoire and worse clinical course, MDSC subtypes (polymorphonuclear, PMN-MDSC, and monocytic, M-MDSCs) were often functionally discordant. In vivo, PMN-MDSCs existed in higher numbers, correlated with different Th-subsets, and more strongly associated with poor clinical course than M-MDSCs. In vitro, PMN-MDSCs were more efficient at blocking T-cell growth and promoted Th17 differentiation. Conversely, in vitro M-MDSCs varied in their ability to suppress T-cell proliferation, due to the action of TNFα, and promoted a more immunostimulatory Th compartment. Ibrutinib therapy impacted MDSCs differentially as well, since after initiating therapy, PMN-MDSC numbers progressively declined, whereas M-MDSC numbers were unaffected, leading to a set of less immunosuppressive Th cells. Consistent with this, clinical improvement based on decreasing CLL-cell numbers correlated with the decrease in PMN-MDSCs. Collectively, the data support a balance between PMN-MDSC and M-MDSC numbers and function influencing CLL disease course.

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Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function

Journal of Experimental Medicine ◽

10.1084/jem.20091474 ◽

2010 ◽

Vol 207 (7) ◽

pp. 1453-1464 ◽

Cited By ~ 205

Author(s):

Leif E. Sander ◽

Sara Dutton Sackett ◽

Uta Dierssen ◽

Naiara Beraza ◽

Reinhold P. Linke ◽

...

Keyword(s):

Acute Phase ◽

Cell Function ◽

Inflammatory Responses ◽

Acute Phase Proteins ◽

Suppressor Cells ◽

Suppressor Cell ◽

Amyloid A ◽

Myeloid Derived Suppressor Cell ◽

Infection And Inflammation ◽

Deficient Mice

Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130–STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection.

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High-dose dexamethasone corrects impaired myeloid-derived suppressor cell function via Ets1 in immune thrombocytopenia

Blood ◽

10.1182/blood-2015-10-674531 ◽

2016 ◽

Vol 127 (12) ◽

pp. 1587-1597 ◽

Cited By ~ 23

Author(s):

Yu Hou ◽

Qi Feng ◽

Miao Xu ◽

Guo-sheng Li ◽

Xue-na Liu ◽

...

Keyword(s):

Immune Thrombocytopenia ◽

Cell Function ◽

Suppressor Cells ◽

Suppressor Cell ◽

High Dose ◽

Myeloid Derived Suppressor Cells ◽

High Dose Dexamethasone ◽

Myeloid Derived Suppressor Cell ◽

Key Points ◽

Therapeutic Mechanism

Key Points The impaired suppressive function of myeloid-derived suppressor cells plays a role in the pathogenesis of immune thrombocytopenia. The effect of dexamethasone in correcting dysfunction of myeloid-derived suppressor cells suggests a new therapeutic mechanism of high-dose dexamethasone in patients with immune thrombocytopenia.

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Myeloid-Derived Suppressor Cell Function in Breast Cancer Patients

Case Medical Research ◽

10.31525/ct1-nct04022616 ◽

2019 ◽

Author(s):

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Cell Function ◽

Suppressor Cell ◽

Breast Cancer Patients ◽

Myeloid Derived Suppressor Cell

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Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice

Journal of Allergy and Clinical Immunology ◽

10.1016/j.jaci.2014.04.035 ◽

2014 ◽

Vol 134 (5) ◽

pp. 1163-1174.e16 ◽

Cited By ~ 26

Author(s):

Maohua Shi ◽

Guochao Shi ◽

Juan Tang ◽

Deping Kong ◽

Yao Bao ◽

...

Keyword(s):

Airway Hyperresponsiveness ◽

Cell Function ◽

Suppressor Cell ◽

Myeloid Derived Suppressor Cell

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Analysis of the Myeloid-Derived Suppressor Cells and Annexin A1 in Multibacillary Leprosy and Reactional Episodes

10.21203/rs.3.rs-126210/v1 ◽

2020 ◽

Author(s):

Amilcar Sabino Damazo ◽

Stephanni Figueiredo da Silva ◽

Leticia Rossetto da Silva Cavalcante ◽

Ezequiel Angelo Fonseca Junior ◽

Joselina Maria da Silva ◽

...

Keyword(s):

Suppressor Cells ◽

Suppressor Cell ◽

Mycobacterium Leprae ◽

Histopathological Analysis ◽

Annexin A1 ◽

Myeloid Derived Suppressor Cells ◽

Myeloid Derived Suppressor Cell ◽

Leprosy Patients ◽

Multibacillary Leprosy

Abstract Background: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Patients have distinct clinical forms, and host´s immunological response regulate those manifestations. In this work, the presence of the myeloid-derived suppressor cell and the regulatory protein annexin A1 is described in patients with multibacillary leprosy and with type 1 and 2 reactions. Methods: Patients were submitted to skin biopsy for histopathological analysis to obtain bacilloscopic index. Immunofluorescence was used to detect myeloid-derived suppressor cells and annexin A1.Results: The data demonstrated that the presence of granulocytic and monocytic myeloid-derived suppressor cells in leprosy patients. The high number of monocytic myeloid-derived suppressor cells were observed in lepromatous leprosy and type 2 reactional patients with Bacillus Calmette–Guérin (BCG) vaccination scar. The presence of annexin A1 was observed in all myeloid-derived suppressor cells. In particularly, the monocytic myeloid-derived suppressor cell in the lepromatous patients has higher levels of this protein when compared to the reactional patients. This data suggest that the higher expression of this protein may be related to regulatory response against a severe infection, contributing to anergic response. In type 1 reactional patients, the expression of annexin A1 was reduced. Conclusions: Myeloid-derived suppressor cell are present in leprosy patients and annexin A1 might be regulated the host response against Mycobacterium leprae.

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Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Metabolites ◽

10.3390/metabo10070289 ◽

2020 ◽

Vol 10 (7) ◽

pp. 289 ◽

Cited By ~ 2

Author(s):

Xun Chen ◽

Shangwu Chen ◽

Dongsheng Yu

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Tumor Cells ◽

Metabolic Regulation ◽

Metabolic Response ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Acid Oxidation ◽

Drug Resistant ◽

Chemotherapy Drugs

Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation.

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