4-1BB Ligand Stimulation Enhances Myeloid Dendritic Cell Maturation from Human Umbilical Cord Blood CD34<sup>+</sup>Progenitor Cells

Kim, Yong Baek; Li, Geling; Broxmeyer, Hal E.

doi:10.1089/152581602321080556

Cited by 41 publications

(41 citation statements)

References 49 publications

(71 reference statements)

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“…As CD137L signalling induces DC differentiation of peripheral human monocytes (Ju et al, 2009;Kwajah & Schwarz, 2010), and maturation of immature DC (Kim et al, 2002;Laderach et al, 2003;Lippert et al, 2008) we investigated whether AML cells would acquire DC-like properties upon exposure to recombinant CD137 protein. When monocytic AML cells, mainly of the M5b subtype and characterized by high CD14 expression, were treated with CD137 protein, the DC marker CD83 was observed to be up-regulated (Fig 4A) while the phagocytic ability of these cells was decreased (Fig 4B).…”

Section: Resultsmentioning

confidence: 99%

“…Further, CD137L signalling induces maturation of immature dendritic cells (DC) (Kim et al, 2002;Laderach et al, 2003;Lippert et al, 2008), and even differentiation of peripheral human monocytes to mature DC (Ju et al, 2009;Kwajah & Schwarz, 2010). These activities of CD137 play a role during infectioninduced myelopoiesis (Tang et al, 2013) and mark CD137 as a potent monocytic differentiation factor.…”

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confidence: 99%

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CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

et al. 2014

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SummaryCD137 ligand (CD137L), a member of the tumour necrosis factor family, is expressed as a cell surface molecule. Engagement of CD137L on haematopoietic progenitor cells induces monocytic differentiation, and in peripheral monocytes CD137L signalling promotes differentiation to mature dendritic cells. We hypothesized that CD137L signalling would also induce differentiation in transformed myeloid cells. Here we show that recombinant CD137 protein, which crosslinks CD137L and initiates reverse CD137L signalling in myeloid cells, induces morphological changes (adherence, spreading), loss of progenitor markers (CD117), expression of maturation markers (CD11b, CD13) and secretion of cytokines that are indicative of myeloid differentiation. Under the influence of CD137L signalling, acute myeloid leukaemia (AML) cells acquired expression of co-stimulatory molecules (CD80, CD86, CD40), the dendritic cell marker CD83 and dendritic cell activities, enabling them to stimulate T cells. CD137L signalling induced differentiation in 71% (15 of 21) of AML samples, irrespective of French-American-British classification and CD137L expression level. However, the type of response varied with the AML subtype and patient sample. In summary, this study demonstrated that CD137L signalling induced differentiation in malignant cells of AML patients, and suggests that it may be worthwhile to investigate treatment with recombinant CD137 protein as a potential novel therapeutic approach for AML.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

et al. 2014

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“…in vitro and in vivo. 4-1BBL is capable of enhancing the expression of B7 molecules on dendritic cells to augment the dendritic cellmediated second signal (B7/CD28 signaling) for T-cell activation (7,8). In particular, 4-1BBL/4-1BB signaling, unlike B7/ CD28, is very important for the effector phase of T-cell response (30 -32).…”

Section: Discussionmentioning

confidence: 99%

Soluble PD-1 Facilitates 4-1BBL–Triggered Antitumor Immunity against Murine H22 Hepatocarcinoma In vivo

Xiao

Huang

Yuan

et al. 2007

Clinical Cancer Research

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Purpose: The use of costimulatory molecules targeting distinct T-cell signaling pathways has provided a means for triggering and enhancing antitumor immunity; however, it is still not fully understood what types of costimulatory molecules are suitable for the combination in tumor therapy. Our purpose in this study is to establish an effective antitumor immune approach by using costimulatory molecule 4-1BBL in combination with soluble PD-1. Experimental Design: The murine H22 hepatocarcinoma served as an ectopic tumor model. Local gene transfer was done by injection with naked plasmid p4-1BBL and/or psPD-1. The synergistic mechanism of dual-gene therapy was elucidated by detecting the change of gene expression of immunoregulatory factors in tumor microenvironment.The effects of immunotherapy were evaluated by testing the function of tumor-specific T cells, measuring tumor weight or volume, survival of mice, and H&E staining of tissues. Results: 4-1BBL expressed by normal nonimmune cells effectively enhanced antitumor immune response but up-regulated PD-L1 and did not reduce IL-10 and transforming growth factor-h (TGF-h). sPD-1synergized with 4-1BBL to establish efficient antitumor immune environment, including down-regulation of IL-10 andTGF-h, further up-regulation of interleukin (IL)-2 and IFN-g, and higher CD8 + T-cell infiltration. The combined treatment by 4-1BBL/sPD-1eradicated tumors from mice with small amounts of preexistent tumor cells or tumors from f60% of individuals with larger amounts of preexistent tumor cells. Conclusions: Our findings in this report imply a great potential of 4-1BBL in combination with sPD-1in tumor therapeutics with the in vivo existent tumor cells as antigens.

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“…Cytotoxicity was determined in a standard 4-hour 51 Cr release assay using an Epstein-Barr virus (EBV)-transformed B-cell line, kindly provided by Dr Karen Pollok (Indiana University, Indianapolis), as target cells. The EBV-transformed B-cell line was derived from human primary B cells by infection with EBV and subsequent incubation in a humidified 37°C, 5% CO 2 incubator for 3 weeks to select immortalized cells.…”

Section: Anti-cd3 Redirected Cytotoxicity Assaymentioning

confidence: 99%

Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation

Kim

Stringfield

Chen

et al. 2005

Blood

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Transforming growth factor-β1 (TGF-β1), an immunosuppressive cytokine, inhibits cytotoxic T cell (CTL) immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the tumor necrosis factor (TNF) receptor family, amplifies CTL-mediated antitumor immune responses. We investigated whether TGF-β1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-β1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-β1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-β1, suggesting that 4-1BB effects were at the level of TGF-β1 signaling. 4-1BB effects on the TGF-β1-mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was up- or down-regulated, respectively, by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-β1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-β1-mediated suppression. (Blood. 2005;105:274-281)

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4-1BB Ligand Stimulation Enhances Myeloid Dendritic Cell Maturation from Human Umbilical Cord Blood CD34⁺Progenitor Cells

Cited by 41 publications

References 49 publications

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

Soluble PD-1 Facilitates 4-1BBL–Triggered Antitumor Immunity against Murine H22 Hepatocarcinoma In vivo

Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation

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4-1BB Ligand Stimulation Enhances Myeloid Dendritic Cell Maturation from Human Umbilical Cord Blood CD34+Progenitor Cells

Cited by 41 publications

References 49 publications

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

CD137 ligand signalling induces differentiation of primary acute myeloid leukaemia cells

Soluble PD-1 Facilitates 4-1BBL–Triggered Antitumor Immunity against Murine H22 Hepatocarcinoma In vivo

Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation

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4-1BB Ligand Stimulation Enhances Myeloid Dendritic Cell Maturation from Human Umbilical Cord Blood CD34⁺Progenitor Cells