Myeloid phenotypes in severe COVID-19 predict secondary infection and mortality: a pilot study

Abstract Background De-regulated host response to severe coronavirus disease 2019 (COVID-19), directly referring to the concept of sepsis-associated immunological dysregulation, seems to be a strong signature of severe COVID-19. Myeloid cells phenotyping is well recognized to diagnose critical illness-induced immunodepression in sepsis and has not been well characterized in COVID-19. The aim of this study is to review phenotypic characteristics of myeloid cells and evaluate their relations with the occurrence of secondary infection and mortality in patients with COVID-19 admitted in an intensive care unit. Methods Retrospective analysis of the circulating myeloid cells phenotypes of adult COVID-19 critically ill patients. Phenotyping circulating immune cells was performed by flow cytometry daily for routine analysis and twice weekly for lymphocytes and monocytes subpopulations analysis, as well as monocyte human leukocyte antigen (mHLA)-DR expression. Results Out of the 29 critically ill adult patients with severe COVID-19 analyzed, 12 (41.4%) developed secondary infection and six patients died during their stay. Monocyte HLA-DR kinetics was significantly different between patients developing secondary infection and those without, respectively, at day 5–7 and 8–10 following admission. The monocytes myeloid-derived suppressor cells to total monocytes ratio was associated with 28- and 60-day mortality. Those myeloid characteristics suggest three phenotypes: hyperactivated monocyte/macrophage is significantly associated with mortality, whereas persistent immunodepression is associated with secondary infection occurrence compared to transient immunodepression. Conclusions Myeloid phenotypes of critically ill COVID-19 patients may be associated with development of secondary infection, 28- and 60-day mortality.

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Characterization of Myeloid-Derived Suppressor Cells and Tumor Associated Macrophages Using MultiOmyxTM Hyperplexed Immunofluorescence Assay in Hodgkin Lymphoma

Blood ◽

10.1182/blood-2018-99-115434 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4135-4135

Author(s):

Qingyan Au ◽

Jun Fang ◽

Anna Juncker-Jensen ◽

Judy Kuo ◽

Eric Leones ◽

...

Keyword(s):

Hodgkin Lymphoma ◽

Hematological Malignancies ◽

Myeloid Cells ◽

Suppressor Cells ◽

Myeloid Cell ◽

Myeloid Derived Suppressor Cells ◽

M2 Macrophages ◽

Tumor Associated Macrophages ◽

Hla Dr

Abstract Tumor microenvironment (TME) consists of heterogeneous subsets of myeloid cells and plays a crucial role in promoting cancer development and metastasis. Tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) all contribute to an immunologically permissive microenvironment for cancer cells. On basis of the expression of surface markers, MDSC can be further subdivided into granulocytic MDSC (G-MDSC, polymorphonuclear MDSC) and monocytic MDSC (M-MDSC). In solid tumors, these different myeloid cell populations are well characterized and extensively studied. However, in hematological malignancies the role of myeloid cell subsets has been less studied. A recent study showed increase in MDSC in the bone marrow (BM) at time of diagnosis in acute myeloid leukemia (AML) patients (Sun H. et al. Int J Hematol. 2015). Significantly higher numbers of G-MDSC and M-MDSC were present at diagnosis in classic Hodgkin lymphoma (cHL) (Romano A. et al. Br J Haematol. 2015). The accumulation of TAMs was also reported to be associated with poor prognosis in cHL (Steidl C. et al. N Engl J Med. 2010). Collectively, these results indicate that the tumor-resident myeloid cells play an important clinical role, thus highlighting the need for monitoring and deeper characterization of various myeloid subsets in hematological malignancies, especially in the tumor FFPE sections. Herein, we report an analysis of MDSCs and 'protumoral' M2 macrophages using MultiOmyx hyperplexed immunofluorescence (IF) assay in 9 clinical samples diagnosed with HL. MultiOmyx is a proprietary multi 'omic' technology that enables detection and visualization of up to 60 biomarkers on a single 4µM FFPE slide (Gerdes MJ. et al. PNAS 2013). The HL FFPE sections were stained with a 13-marker panel including Arginase 1, CD11b, CD14, CD15, CD16, CD33, CD68, CD163, HLA-DR, CD3, CD4, CD8 and FOXP3. We observed that both M-MDSC (Fig 1A, characterized as CD11b+CD14+CD15-CD33+HLA-DR-) and G-MDSC (Fig 1B, identified as CD11b+CD14-CD15+CD33+HLA-DR-) accumulated within the TME in all 9 HL samples, with higher frequency of G-MDSCs over M-MDSCs. Arg1 expression was detected exclusively in G-MDSC population (Fig 1C). The data also revealed an abundant M2 macrophages (Fig 1D, characterized as CD68+CD163+) present in all HL samples. The detection of both MDSCs and M2 macrophages in HL samples supports the hypothesis that these cells contribute to the establishment of an immunosuppressive TME. Using the MultiOmyx proprietary algorithm, which takes into account the staining patterns, we will next quantify the counts and density of different tumor-resident myeloid subsets and measure the spatial distance between each subset of tumor-resident myeloid cells to the neoplastic Reed-Sternberg cells. Correlation study will also be performed to determine if significant correlations exist between MDSCs and TAMs and how these immunosuppressive myeloid cells are related to the Regulatory T cells (CD3+CD4+FOXP3+) in HL samples. In addition to HL samples, the same 13-plexed panel will be utilized to characterize the myeloid cell population from AML patients. TAMs and MDSCs are emerging as potential biomarkers for diagnosis and prognosis of cancer as well as therapeutic targets. The comprehensive myeloid cells phenotyping offered by MultiOmyx 13-plexed panel has the potential to monitor the changes of immunosuppressive myeloid cells in response to immune modulating drugs such as MDSC-targeting drugs (e.g. PDE-5 inhibitors, COX-2 inhibitors), TAM-targeting agents (e.g. anti-CSF1R) and combined therapy in treatment of lymphoma and leukemia. Disclosures No relevant conflicts of interest to declare.

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Insufficient Nutrition and Mortality Risk in Septic Patients Admitted to ICU with a Focus on Immune Dysfunction

Nutrients ◽

10.3390/nu11020367 ◽

2019 ◽

Vol 11 (2) ◽

pp. 367 ◽

Cited By ~ 4

Author(s):

Kai-Yin Hung ◽

Yu-Mu Chen ◽

Chin-Chou Wang ◽

Yi-Hsi Wang ◽

Chiung-Yu Lin ◽

...

Keyword(s):

Synergistic Effect ◽

Critically Ill ◽

Prospective Observational Study ◽

Caloric Intake ◽

Human Leukocyte ◽

Immune Dysfunction ◽

Leukocyte Antigen ◽

Hla Dr ◽

Failure Assessment ◽

Baseline Characteristics

Immune dysfunction is seen both in sepsis patients and in those with malnutrition. This study aimed to determine whether insufficient nutrition and immune dysfunction have a synergistic effect on mortality in critically ill septic patients. We conducted a prospective observational study from adult sepsis patients admitted to intensive care units (ICUs) between August 2013 and June 2016. Baseline characteristics including age, gender, body mass index, NUTRIC, Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores were recorded. Immune dysfunction, defined by human leukocyte antigen DR (HLA-DR) expression, was tested at days 1, 3, and 7 of ICU admission. The study included 151 patients with sepsis who were admitted to the ICU. The 28-day survivors had higher day 7 caloric intakes (89% vs 73%, p = 0.042) and higher day 1-HLA-DR expression (88.4 vs. 79.1, p = 0.045). The cut-off points of day 7 caloric intake and day 1-HLA-DR determined by operating characteristic curves were 65.1% and 87.2%, respectively. Immune dysfunction was defined as patients with day 1-HLA-DR < 87.2%. Insufficient nutrition had no influence on survival outcomes in patients with immune dysfunction. However, patients with insufficient nutrition had poor prognosis when they were immune competent. Insufficient nutrition and immune dysfunction did not have a synergistic effect on mortality in critically ill septic patients.

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CD14+ CD15− HLA-DR− myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure

Gut ◽

10.1136/gutjnl-2017-314184 ◽

2017 ◽

Vol 67 (6) ◽

pp. 1155-1167 ◽

Cited By ~ 31

Author(s):

Christine Bernsmeier ◽

Evangelos Triantafyllou ◽

Robert Brenig ◽

Fanny J Lebosse ◽

Arjuna Singanayagam ◽

...

Keyword(s):

T Cell ◽

Liver Failure ◽

Immune Function ◽

Secondary Infection ◽

Suppressor Cells ◽

Innate Immune ◽

Myeloid Derived Suppressor Cells ◽

Chronic Liver Failure ◽

Innate Immune Function ◽

Hla Dr

ObjectiveImmune paresis in patients with acute-on-chronic liver failure (ACLF) accounts for infection susceptibility and increased mortality. Immunosuppressive mononuclear CD14+HLA-DR− myeloid-derived suppressor cells (M-MDSCs) have recently been identified to quell antimicrobial responses in immune-mediated diseases. We sought to delineate the function and derivation of M-MDSC in patients with ACLF, and explore potential targets to augment antimicrobial responses.DesignPatients with ACLF (n=41) were compared with healthy subjects (n=25) and patients with cirrhosis (n=22) or acute liver failure (n=30). CD14+CD15−CD11b+HLA-DR− cells were identified as per definition of M-MDSC and detailed immunophenotypic analyses were performed. Suppression of T cell activation was assessed by mixed lymphocyte reaction. Assessment of innate immune function included cytokine expression in response to Toll-like receptor (TLR-2, TLR-4 and TLR-9) stimulation and phagocytosis assays using flow cytometry and live cell imaging-based techniques.ResultsCirculating CD14+CD15−CD11b+HLA-DR− M-MDSCs were markedly expanded in patients with ACLF (55% of CD14+ cells). M-MDSC displayed immunosuppressive properties, significantly decreasing T cell proliferation (p=0.01), producing less tumour necrosis factor-alpha/interleukin-6 in response to TLR stimulation (all p<0.01), and reduced bacterial uptake of Escherichia coli (p<0.001). Persistently low expression of HLA-DR during disease evolution was linked to secondary infection and 28-day mortality. Recurrent TLR-2 and TLR-4 stimulation expanded M-MDSC in vitro. By contrast, TLR-3 agonism reconstituted HLA-DR expression and innate immune function ex vivo.ConclusionImmunosuppressive CD14+HLA-DR− M-MDSCs are expanded in patients with ACLF. They were depicted by suppressing T cell function, attenuated antimicrobial innate immune responses, linked to secondary infection, disease severity and prognosis. TLR-3 agonism reversed M-MDSC expansion and innate immune function and merits further evaluation as potential immunotherapeutic agent.

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Identification of CD4+CD25+CD127− regulatory T cells and CD14+HLA−DR−/low myeloid-derived suppressor cells and their roles in the prognosis of breast cancer

Biomedical Reports ◽

10.3892/br.2016.694 ◽

2016 ◽

Vol 5 (2) ◽

pp. 208-212 ◽

Cited By ~ 9

Author(s):

Jinhu Wang ◽

Jianhong Yang

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Hla Dr

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Granulocytic myeloid-derived suppressor cells inversely correlate with plasma arginine and overall survival in critically ill patients

Clinical & Experimental Immunology ◽

10.1111/cei.12567 ◽

2015 ◽

Vol 180 (2) ◽

pp. 280-288 ◽

Cited By ~ 16

Author(s):

A. Gey ◽

J.-M. Tadie ◽

A. Caumont-Prim ◽

C. Hauw-Berlemont ◽

L. Cynober ◽

...

Keyword(s):

Overall Survival ◽

Critically Ill ◽

Critically Ill Patients ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Plasma Arginine

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Abstract 87: The Accumulation of Myeloid-derived Suppressor Cells Is a Compensatory Response to the Development of Hypertension

Hypertension ◽

10.1161/hyp.62.suppl_1.a87 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Xiao Z Shen ◽

Peng Shi ◽

Jorge Giani ◽

Ellen Bernstein ◽

Kenneth E Bernstein

Keyword(s):

Blood Pressure ◽

T Cell ◽

Angiotensin Ii ◽

Critical Role ◽

Myeloid Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Compensatory Response ◽

Immunosuppressive Cell ◽

Induced Hypertension

The immune system plays a critical role in the development of hypertension. The immune response consists of pro-inflammatory cells, but also immunosuppressive cells that reduce T cell function. An important category of natural immunosuppressive cell is myeloid-derived suppressor cells (MDSC). We now show that blood and spleen CD11b+ Gr1+ myeloid cells are elevated 2-fold in both angiotensin II and L-NAME induced hypertension. These increased myeloid cells are MDSC in that they elevate IL-4R expression and suppress T cell proliferation. When hypertensive mice were depleted of MDSC, using either anti-Gr1 antibody or gemcitabine, there was a 15 mmHg rise in blood pressure and aggravation of T cells activation with increased production of IFN-γ, TNFα and IL-17 in both spleen and kidney. In contrast, adoptive transfer of MDSC reduced blood pressure in angiotensin-II induced hypertension by 25 mmHg (see Figure). These data suggest a new concept, that the accumulation of MDSC is a compensatory response to the inflammation induced by hypertension. They also indicate that MDSC play an important role in regulating blood pressure.

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