Bifidobacterial Species Differentially Affect Expression of Cell Surface Markers and Cytokines of Dendritic Cells Harvested from Cord Blood

ABSTRACT The gut microbiota may be important in the postnatal development of the immune system and hence may influence the prevalence of atopic diseases. Bifidobacteria are the most numerous bacteria in the guts of infants, and the presence or absence of certain species could be important in determining the geographic incidence of atopic diseases. We compared the fecal populations of bifidobacteria from children aged 25 to 35 days in Ghana (which has a low prevalence of atopy), New Zealand, and the United Kingdom (high-prevalence countries). Natal origin influenced the detection of bifidobacterial species in that fecal samples from Ghana almost all contained Bifidobacterium infantis whereas those of the other children did not. Choosing species on the basis of our bacteriological results, we tested bifidobacterial preparations for their effects on cell surface markers and cytokine production by dendritic cells harvested from cord blood. Species-specific effects on the expression of the dendritic-cell activation marker CD83 and the production of interleukin-10 (IL-10) were observed. Whereas CD83 expression was increased and IL-10 production was induced by Bifidobacterium bifidum, Bifidobacterium longum, and Bifidobacterium pseudocatenulatum, B. infantis failed to produce these effects. We concluded that B. infantis does not trigger the activation of dendritic cells to the degree necessary to initiate an immune response but that B. bifidum, B. longum, and B. pseudocatenulatum induce a Th2-driven immune response. A hypothesis is presented to link our observations to the prevalence of atopic diseases in different countries.

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CELL SURFACE MARKERS IN CORD BLOOD LEUCOCYTES AFTER STIMULATION WITH LIPOPOLYSACCHARIDE B

Acta Pathologica Microbiologica Scandinavica Section C Immunology ◽

10.1111/j.1699-0463.1978.tb02596.x ◽

2009 ◽

Vol 86C (1-6) ◽

pp. 315-319

Author(s):

J. SchröDer ◽

O. Turunen ◽

C. Lundqvist ◽

A. Chapelle

Keyword(s):

Cell Surface ◽

Cord Blood ◽

Surface Markers ◽

Cell Surface Markers

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Cell surface markers and cellular immune response associated with rheumatic heart disease: Complex segregation analysis

Genetic Epidemiology ◽

10.1002/gepi.1370050610 ◽

1988 ◽

Vol 5 (6) ◽

pp. 463-470 ◽

Cited By ~ 3

Author(s):

SS Rich ◽

ED Gray ◽

R. Talbot ◽

D. Martin ◽

L. Cairns ◽

...

Keyword(s):

Immune Response ◽

Heart Disease ◽

Cell Surface ◽

Cellular Immune Response ◽

Segregation Analysis ◽

Surface Markers ◽

Cell Surface Markers ◽

Complex Segregation Analysis ◽

Cellular Immune ◽

Rheumatic Heart

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IRAK-M modulates expression of IL-10 and cell surface markers CD80 and MHC II after bacterial re-stimulation of tolerized dendritic cells

Immunology Letters ◽

10.1016/j.imlet.2012.03.006 ◽

2012 ◽

Vol 144 (1-2) ◽

pp. 49-59 ◽

Cited By ~ 15

Author(s):

Tyler S. Cole ◽

Min Zhang ◽

Theodore J. Standiford ◽

Michael Newstead ◽

Jay Luther ◽

...

Keyword(s):

Dendritic Cells ◽

Cell Surface ◽

Surface Markers ◽

Cell Surface Markers ◽

Mhc Ii ◽

Stimulation Of

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784 BDC-2034: discovery of a CEA-targeting immune-stimulating antibody conjugate (ISAC) for solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.784 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A819-A819

Author(s):

William Mallet ◽

Rishali Gadkari ◽

Cecelia Pearson ◽

Laughing Bear Torrez Dulgeroff ◽

Angela Luo ◽

...

Keyword(s):

Immune Response ◽

Cell Surface ◽

Tumor Cell ◽

Solid Tumors ◽

Cell Activation ◽

Cell Surface Expression ◽

List Type ◽

Dendritic Cell Activation ◽

Antibody Conjugates

BackgroundCEA (CEACAM5) is a well-validated cell-surface antigen that is highly expressed in multiple solid tumors. Bolt's immune-stimulating antibody conjugates (ISACs) direct a TLR7/8 agonist into tumors to activate tumor-infiltrating myeloid cells and initiate a broad innate and adaptive anti-tumor immune response.1 The favorable properties of CEA, including robust cell surface expression, low internalization rate, and limited normal tissue expression, suggest that the antigen may be a suitable ISAC target. We are evaluating an anti-CEA ISAC, BDC-2034, as a multi-functional approach to treat CEA-expressing cancers.MethodsAnti-CEA antibodies were tested for binding affinity and specificity, CEA-targeted antibody-dependent cellular phagocytosis (ADCP), and myeloid-mediated tumor cell killing. Selected antibodies were conjugated to proprietary TLR7/8 agonists, and the resulting CEA ISACs were evaluated for in vitro myeloid activation and in vivo efficacy against xenograft tumors.ResultsAntibody CEA1 binds to the CEA protein with high affinity (EC50 = 0.25 nM), binds selectively to CEA-positive tumor cell lines, and mediates ADCP more efficiently than a reference anti-CEA antibody, labetuzumab (figure 1). We generated BDC-2034 by conjugating a potent TLR7/8 agonist to CEA1. BDC-2034 tumor cell binding drives myeloid effector cell ADCP, agonist delivery to TLR7 and TLR8 in endosomes, and secretion of cytokines critical for innate and adaptive immunity (including IL-12p70, CXCL10, and TNFa). In the HPAF II + cDC co-culture model, IL-12p70 is induced with EC50 = 1.2 nM, and the level of induction is at least ten-fold higher than with ISACs using labetuzumab (figure 2). Potent cellular activity is strictly dependent on tumor cell CEA expression; in whole blood, in the absence of CEA-expressing tumor cells, cytokine induction was only observed at approximately 100-fold higher concentrations. BDC-2034 inhibits the growth of HPAF II xenograft tumors in SCID/beige mice with a minimal efficacious dose (MED) of 1 mg/kg, demonstrating anti-tumor activity solely through innate immune activation (figure 3). The TLR7/8 agonist in BDC-2034 has relatively poor activity in mice; a surrogate CEA1 ISAC with a mouse TLR7-activating agonist achieved MED = 0.5 mg/kg in the HPAF II model, with eradication of all tumors at the 5 mg/kg dose.ConclusionsThese pre-clinical data demonstrate the potential of BDC-2034 to treat CEA-expressing human cancers. Most importantly, the antigen-dependent induction of immune-stimulating cytokines promises a robust immune response that combines the activation of innate and adaptive arms.ReferenceAckerman S, Pearson C, Gregorio J. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nature Cancer 2021;2:18–33. https://doi.org/10.1038/s43018-020-00136-xAbstract 784 Figure 1ADCP. Anti-CEA antibody CEA1 is an efficient inducer of ADCP of Raji/CEA cells by M-CSF differentiated monocyte-derived macrophagesAbstract 784 Figure 2Tumor-dependent dendritic cell activation. BDC-2034 induces IL-12p70 secretion from primary dendritic cells (cDC); native CEA1 antibody and reference anti-CEA ISAC are ineffectiveAbstract 784 Figure 3Efficacy against xenograft tumors. BDC-2034 inhibits the growth of HPAF II tumors in SCID/beige mice; native CEA1 antibody and isotype ISAC are ineffective

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