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

Critical Care ◽  
2019 ◽  
Vol 23 (1) ◽  
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.

scholarly journals Cholangiocarcinoma presents a distinct myeloid-derived suppressor cell signature compared to other hepatobiliary cancers

2019 ◽  
Author(s):  
Defne Bayik ◽  
Adam J. Lauko ◽  
Gustavo A. Roversi ◽  
Emily Serbinowski ◽  
Lou-Anne Acevedo-Moreno ◽  
...  
Keyword(s):  
Suppressor Cells ◽  
Myeloid Cell ◽  
Suppressor Cell ◽  
The Cancer Genome Atlas ◽  
Limiting Factor ◽  
Isocitrate Dehydrogenase 1 ◽  
Myeloid Derived Suppressor Cell ◽  
Liver Cancers ◽  
Malignant Liver ◽  
Immunosuppressive Cells

AbstractMyeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSC in other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). Investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of the Cancer Genome Atlas demonstrated that a high MDSC score in HCC patients predicted poor disease outcome. Mechanistic studies indicated that the oncometabolite D-2-hydroxyglutarate resulting from isocitrate dehydrogenase 1 mutation could be a limiting factor of MDSC accumulation in CCA patients. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, they may comprise suitable targets for effective immunotherapy approaches.

scholarly journals Hepatobiliary malignancies have distinct peripheral myeloid-derived suppressor cell signatures and tumor myeloid cell profiles

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Defne Bayik ◽  
Adam J. Lauko ◽  
Gustavo A. Roversi ◽  
Emily Serbinowski ◽  
Lou-Anne Acevedo-Moreno ◽  
...  
Keyword(s):  
Suppressor Cells ◽  
Myeloid Cell ◽  
Suppressor Cell ◽  
The Cancer Genome Atlas ◽  
Hepatobiliary Malignancies ◽  
Myeloid Derived Suppressor Cell ◽  
Liver Cancers ◽  
Malignant Liver ◽  
Immunosuppressive Cells ◽  
Antigen Presenting

Abstract Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells that are increased in patients with numerous malignancies including viral-derived hepatocellular carcinoma (HCC). Here, we report an elevation of MDSCs in the peripheral blood of patients with other hepatobiliary malignancies including non-viral HCC, neuroendocrine tumors (NET), and colorectal carcinoma with liver metastases (CRLM), but not cholangiocarcinoma (CCA). The investigation of myeloid cell infiltration in HCC, NET and intrahepatic CCA tumors further established that the frequency of antigen-presenting cells was limited compared to benign lesions, suggesting that primary and metastatic hepatobiliary cancers have distinct peripheral and tumoral myeloid signatures. Bioinformatics analysis of The Cancer Genome Atlas dataset demonstrated that a high MDSC score in HCC patients is associated with poor disease outcome. Given our observation that MDSCs are increased in non-CCA malignant liver cancers, these cells may represent suitable targets for effective immunotherapy approaches.

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

Leukemia ◽  
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.

scholarly journals Metabolic Regulation of Myeloid-Derived Suppressor Cell Function in Cancer

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1011 ◽  
Author(s):  
Yufei Wang ◽  
Anna Jia ◽  
Yujing Bi ◽  
Yuexin Wang ◽  
Guangwei Liu
Keyword(s):  
Metabolic Regulation ◽  
Cell Function ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Immune Recognition ◽  
T Cell Apoptosis ◽  
Inhibitory Function ◽  
Myeloid Derived Suppressor Cell

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.

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

2010 ◽  
Vol 207 (7) ◽  
pp. 1453-1464 ◽  
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.

scholarly journals Myeloid-derived Suppressor Cell and Non-classical Monocyte Frequencies Are Directly Related to the Immunological Status of Patients With Active Tuberculosis

2021 ◽  
Author(s):  
Nicolas Amiano ◽  
Joaquín Pellegrini ◽  
María Morelli ◽  
Agustín Rolandelli ◽  
Camila Martinena ◽  
...  
Keyword(s):  
Severe Disease ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Suppressor Cell ◽  
Cell Populations ◽  
Whole Cell Lysate ◽  
Immunological Status ◽  
Myeloid Derived Suppressor Cell ◽  
Healthy Donors ◽  
Classical Monocytes

Abstract Alterations of myeloid cell populations have been reported in patients with tuberculosis (TB). Since myeloid-derived suppressor cells (MDSC) and non-classical monocytes (CD14+CD16+) seem to play an important role in TB, we studied the relationship between these cells and the immunological status of patients. TB patients were classified as high responders (HR-TB) or low responders (LR-TB) according to their T cell responses against a whole cell lysate of Mycobacterium tuberculosis (Mtb-Ag). Thus, LR-TB, individuals with severe disease, display a weaker immune response to Mtb compare to HR-TB, subjects with strong immunity against the bacteria. We observed that LR-TB presented higher percentages of CD14+CD16+ monocytes as compared to HR-TB and healthy donors (HD). Moreover, monocyte-like (M-MDSC) and polymorphonuclear-like MDSC (PMN-MDSC) were increased in TB patients as compared to HD. Furthermore, the proportion of M-MDSC of TB patients inversely correlated with the levels of IFN-γ released after Mtb-Ag stimulation. We also found that LR-TB displayed the highest levels of circulating M-MDSC. Interestingly, in LR-TB, the frequencies of non-classical monocytes and M-MDSC were restored after only three weeks of anti-TB treatment. Together, our findings show a direct relationship between the immunological status of TB patients and the levels of different circulating myeloid cell populations.

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

Blood ◽  
2016 ◽  
Vol 127 (12) ◽  
pp. 1587-1597 ◽  
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.

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

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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