Expression of Soluble Vascular Endothelial Growth Factor Receptor-1 in Human Monocyte-Derived Mature Dendritic Cells Contributes to Their Antiangiogenic Property

Kishuku, Masatoshi; Nishioka, Yasuhiko; Abe, Shinji; Kishi, Jun; Ogino, Hirokazu; Aono, Yoshinori; Azuma, Momoyo; Kinoshita, Katsuhiro; Rentsenhand, Batmungh; Makino, Hideki; Ranjan, Priya; Minakuchi, Kazuo; Sone, Saburo

doi:10.4049/jimmunol.0803849

Cited by 28 publications

(33 citation statements)

References 33 publications

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“…A recent interesting study showed that monocytederived human mature DCs activated by TNF-a or soluble CD40L with IFN-g, but not immature ones, expressed considerable amount of sFLT-1 and showed antiangiogenic potential, significantly inhibiting tumor growth of immunodeficient mice (32). Similar positive function of DC-derived sFLT-1 against VEGF-A/VPF was also reported by other groups (33), suggesting that mature DCs might be resistant to VEGF-A/VPF-mediated functional suppression.…”

Section: Discussionmentioning

confidence: 99%

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

Shimada

Kakeji

Tsujitani

et al. 2011

Molecular Cancer Therapeutics

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Malignant ascitis (MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers. Using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A/vascular permeability factor and its decoy receptor, soluble fms-like tryrosine kinase receptor-1 (sFLT-1), was a major cause of MA resistance to dendritic cell (DC)-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene-deleted recombinant Sendai virus (rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors. These findings were not seen in immunodeficient mice, indicating that a VEGF-A/sFLT-1 imbalance is critical for determining the antitumor immune response by DC-vaccination therapy against MA.

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Section: Discussionmentioning

confidence: 99%

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

Shimada

Kakeji

Tsujitani

et al. 2011

Molecular Cancer Therapeutics

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“…The method by which SCID mouse splenocytes were harvested was the same as that of rat splenocytes. Human PBMCs (MNC) were obtained from leukocytes in lymphocyte separation medium (Litton Bionetics, Kensington, MD) as previously described (42). Leukocytes were separated from peripheral blood of healthy donors using an RS-6600 rotor of a Kubota KR-400 centrifuge (Kubota, Tokyo, Japan).…”

Section: Preparation Of Effector Cellsmentioning

confidence: 99%

A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody

Abe

Morita

Kaneko

et al. 2013

The Journal of Immunology

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Podoplanin (Aggrus), which is a type I transmembrane sialomucin-like glycoprotein, is highly expressed in malignant pleural mesothelioma (MPM). We previously reported the generation of a rat anti-human podoplanin Ab, NZ-1, which inhibited podoplanin-induced platelet aggregation and hematogenous metastasis. In this study, we examined the antitumor effector functions of NZ-1 and NZ-8, a novel rat-human chimeric Ab generated from NZ-1 including Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity against MPM in vitro and in vivo. Immunostaining with NZ-1 showed the expression of podoplanin in 73% (11 out of 15) of MPM cell lines and 92% (33 out of 36) of malignant mesothelioma tissues. NZ-1 could induce potent ADCC against podoplanin-positive MPM cells mediated by rat NK (CD161a+) cells, but not murine splenocytes or human mononuclear cells. Treatment with NZ-1 significantly reduced the growth of s.c. established tumors of MPM cells (ACC-MESO-4 or podoplanin-transfected MSTO-211H) in SCID mice, only when NZ-1 was administered with rat NK cells. In in vivo imaging, NZ-1 efficiently accumulated to xenograft of MPM, and its accumulation continued for 3 wk after systemic administration. Furthermore, NZ-8 preferentially recognized podoplanin expressing in MPM, but not in normal tissues. NZ-8 could induce higher ADCC mediated by human NK cells and complement-dependent cytotoxicity as compared with NZ-1. Treatment with NZ-8 and human NK cells significantly inhibited the growth of MPM cells in vivo. These results strongly suggest that targeting therapy to podoplanin with therapeutic Abs (i.e., NZ-8) derived from NZ-1 might be useful as a novel immunotherapy against MPM.

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“…Soluble Flt1 (sFlt1), a circulating form of VEGF-R1 that lacks the transmembrane domain of the intact protein, results from an alternative splicing of VEGF-R1 and also likely results from the cleavage of membrane-bound Flt1 ectodomain by the disintegrin and metalloproteinase/TNF-a-converting enzyme (ADAM/TACE) family of metalloproteases. 17 sFlt1 is mainly secreted by monocytes, 18,19 endothelial cells, and placental cytotrophoblasts 20 and displays potent inhibitory effects on VEGF. Elevated levels of sFlt1 lead to functional VEGF deficiency and promote an effective antiangiogenic state, which may be of significant clinical importance, as demonstrated by the association of elevated serum sFlt1 levels with placental vascular dysfunction and preeclampsia.…”

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confidence: 99%

Elevated Soluble Flt1 Inhibits Endothelial Repair in PR3-ANCA–Associated Vasculitis

Roux

Pepper²,

Néel³

et al. 2012

Journal of the American Society of Nephrology

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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis exhibits endothelial damage, but the capacity for vessel repair in this disorder is not well understood. Here, we observed a marked increase in serum levels of soluble Flt1 (sFlt1), a potent inhibitor of vascular endothelial growth factor, in patients with active ANCA-associated vasculitis compared with patients during remission and other controls. Serum levels of sFlt1 correlated with C5a, an anaphylatoxin released after complement activation. Serum from patients with acute ANCA-associated vasculitis disrupted blood flow in the chicken chorioallantoic membrane assay, suggesting an antiangiogenic effect. Preincubation with excess human vascular endothelial growth factor prevented this effect. Anti-proteinase-3 (PR3) mAb and serum containing PR3-ANCA from patients with active vasculitis both induced a significant and sustained release of sFlt1 from monocytes, whereas anti-myeloperoxidase (MPO) mAb or polyclonal antibodies did not. However, the serum containing polyclonal PR3-ANCA did not induce release of sFlt1 from cultured human umbilical vein endothelial cells. In summary, these data suggest that anti-PR3 antibodies, and to a much lesser extent anti-MPO antibodies, increase sFlt1 during acute ANCA-associated vasculitis, leading to an antiangiogenic state that hinders endothelial repair.

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Expression of Soluble Vascular Endothelial Growth Factor Receptor-1 in Human Monocyte-Derived Mature Dendritic Cells Contributes to Their Antiangiogenic Property

Cited by 28 publications

References 33 publications

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

Antagonism of VEGF by Genetically Engineered Dendritic Cells Is Essential to Induce Antitumor Immunity against Malignant Ascites

A Novel Targeting Therapy of Malignant Mesothelioma Using Anti-Podoplanin Antibody

Elevated Soluble Flt1 Inhibits Endothelial Repair in PR3-ANCA–Associated Vasculitis

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