CD40ligand‐expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo

Gonzalez‐Carmona, Maria A.; Lukacs‐Kornek, Veronika; Timmerman, A.; Shabani, S.; Kornek, Miroslaw; Vogt, Annabelle; Yildiz, Yildiz; Sievers, Elisabeth; Schmidt‐Wolf, Ingo G.H.; Caselmann, Wolfgang H.; Sauerbruch, Tilman; Schmitz, Volker

doi:10.1002/hep.22296

Cited by 53 publications

(41 citation statements)

References 31 publications

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“…The present study has the following characteristics: First, the co-expression of CD40L and IL-2 was demonstrated to enhance the antitumor effect. Consistent with this, CD40L expressed alone with an adenovirus vector has been demonstrated to effectively induce an antitumor immune response (22); however, marked proliferation of CTLs requires the stimulation of a variety of lymphocyte proliferation factors following production of tumor specific CTLs by DC stimulation, particularly IL-2. However, DCs and CD4 + T lymphocytes also produce certain quantities of IL-2, although exogenous expression of IL-2 exerts more stable and durable functions.…”

Section: Discussionmentioning

confidence: 65%

Adenovirus co-expressing CD40 ligand and interleukin (IL)-2 contributes to maturation of dendritic cells and production of IL-12

et al. 2016

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Abstract. The aim of the present study was to construct a chimeric adenovirus (Ad)5/F35 co-expressing human CD4O ligand (CD4OL) and interleukin (IL)-2 (Ad5/F35 CD40L-IL-2). The infection efficiency to human monocyte-derived dendritic cells (Mo-DCs), expression of genes, phenotype changes and IL-12 production of Mo-DC by Ad5/F35 CD40L-IL-2 were investigated. CD40L and IL-2 from total RNA extracted from human peripheral blood mononuclear cells (PBMCs) were cloned by reverse transcription-polymerase chain reaction and used to construct Ad5/F35 CD40L-IL-2. The infection efficiency, expression of CD40L, and phenotype changes of Mo-DC infected with Ad5/F35 CD40L-IL-2 were analyzed using flow cytometry. The quantities of IL-2 and IL-12 in the supernatants of Mo-DC following infection of Ad5/F35 CD40L-IL-2 were measured by enzyme-linked immunosorbent assay. The CD40L and IL-2 genes were successfully cloned and the Ad5/F35 CD40L-IL-2 was constructed. Ad5/F35 CD40L-IL-2 efficiently infected Mo-DCs with an infection efficiency of >75%, and the infected Mo-DCs expressed CD40L and secreted IL-2. The expression levels of cluster of differentiation (CD)80, CD86, CD40, and human leukocyte antigen-antigen D related on Mo-DC were moderate; however, CD83 was low prior to infection of Ad5/ F35 CD40L-IL-2. Those molecules, particularly CD83, were markedly upregulated 24 h after the infection. Increasing quantities of IL-12 in the supernatants were detected subsequent to infection at different time points in a time-dependent manner. Thus, Ad5/F35 CD40L-IL-2 efficiently infected human Mo-DCs and its products, CD40L and IL-2, were subsequently expressed. In addition, infection with Ad5/F35 CD40L-IL-2 stimulated the maturation of Mo-DC and high levels of IL-12 production.

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Section: Discussionmentioning

confidence: 65%

Adenovirus co-expressing CD40 ligand and interleukin (IL)-2 contributes to maturation of dendritic cells and production of IL-12

et al. 2016

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“…In this regard, we and others have previously shown that dendritic cells, memory T cells, cytotoxic T cells, and gdT cells dwelling in the tumor bed tend to reduce hepatocellular carcinoma (HCC) growth (3)(4)(5)(6)(7), whereas M2 macrophages, N2 neutrophils, Th17 cells, and Foxp3 þ regulatory T cells may stimulate HCC progression (8)(9)(10)(11). These findings are in accordance with the general view that hepatocellular carcinoma is an immunogenic tumor, and provide a rationale for designing immunotherapies for HCC treatment.…”

Section: Introductionmentioning

confidence: 97%

Margin-Infiltrating CD20+ B Cells Display an Atypical Memory Phenotype and Correlate with Favorable Prognosis in Hepatocellular Carcinoma

Shi

Gao

Wang

et al. 2013

Clinical Cancer Research

175

161

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Purpose: The role of infiltrating B cells in hepatocellular carcinoma has been overlooked for many years. This study is aimed to delineate the distribution, prognostic value, and functional status of B cells in human hepatocellular carcinoma.Experimental design: Immunohistochemistry was used to investigate the distribution and clinical significance of infiltrating CD20þ B cells in a series of 120 patients with hepatocellular carcinoma. The results were further tested in an independent series of 200 patients with hepatocellular carcinoma. The functional status of CD20 þ B cells was determined by flow cytometry, immunofluorescence, and in vitro coculture assay.Results: Infiltrating CD20 þ B cells were predominantly concentrated in the tumor invasive margin, compared with the peri-and intratumor areas. High density of margin-infiltrating B lymphocytes (MIL-B) positively correlated with small tumor size, absence of vascular invasion, and increased density of CD8 þ T cells (P < 0.05). Survival analyses revealed that increased number of MIL-Bs and their penetration through the tumor capsule were significantly associated with improved overall and recurrence-free survival, and were identified as independent prognosticators for patients with hepatocellular carcinoma (P < 0.05). Importantly, the results were further validated in another independent hepatocellular carcinoma cohort. Moreover, we found that MIL-Bs featured an atypical memory phenotype (IgDexpressed surface markers characteristic of antigen-presenting cells, possessed tumor-killing potential by producing IFN-g, interleukin 12p40 (IL-12p40), granzyme B, and TRAIL, and acted in cooperation with CD8 þ T cells. Conclusions:The profile of CD20 þ B cells in situ is a new predictor of prognosis for patients with hepatocellular carcinoma and provides a novel target for an optimal immunotherapy against this fatal malignancy.

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“…However, in clinical trials, although TAA-loaded DCs evoked immunological responses in patients with HCC, therapeutic effects were limited [81] . If the DCs were engineered to express CD40L, their anti-tumoral efficacy would be improved against hepatocellular tumors [82] .…”

Section: Intrahepatic Adaptive Immune Responses Against Tumorsmentioning

confidence: 99%

Immunology of Liver

Tian

Chen

2012

Primary Liver Cancer

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CD40ligand‐expressing dendritic cells induce regression of hepatocellular carcinoma by activating innate and acquired immunity in vivo

Cited by 53 publications

References 31 publications

Adenovirus co-expressing CD40 ligand and interleukin (IL)-2 contributes to maturation of dendritic cells and production of IL-12

Adenovirus co-expressing CD40 ligand and interleukin (IL)-2 contributes to maturation of dendritic cells and production of IL-12

Margin-Infiltrating CD20+ B Cells Display an Atypical Memory Phenotype and Correlate with Favorable Prognosis in Hepatocellular Carcinoma

Immunology of Liver

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