Interferon-α-inducible Dendritic Cells Matured with OK-432 Exhibit TRAIL and Fas Ligand Pathway-mediated Killer Activity

Koya, Terutsugu; Yanagisawa, Ryu; Higuchi, Yumiko; Sakai, Kenji; Shimodaira, Shigetaka

doi:10.1038/srep42145

Cited by 14 publications

(25 citation statements)

References 57 publications

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“…Between August 2013 and March 2016, patients with pancreatic cancer were consecutively enrolled in this study. During this period, patients with several types of cancer received the WT1-DC vaccine at the Center for Advanced Cell Therapy in Shinshu University Hospital (26). We selected those with pancreatic cancer who underwent resection after initial diagnosis and then received chemotherapy.…”

Section: Methodsmentioning

confidence: 99%

WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study

Yanagisawa

Koizumi

Koya

et al. 2018

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Abstract. Background/Aim: Wilms' tumor 1 (WT1) is a tumor-associated antigen highly expressed in cancer. We examined the safety of WT1-peptide pulsed dendritic cell (WT1-DC) vaccine in combination withAlthough several treatment approaches, such as surgery and chemotherapy, have been used for treating pancreatic cancer, its prognosis remains poor, and further improvement in the treatment outcome is required (1-4). Recently, immunotherapy has been put forward as a new treatment approach for such cancer types with poor prognosis, and various methods have been examined in practice (1, 2, 5-7). In immunotherapy, selection of the tumor-associated antigen (TAA) is important. It has been reported that the Wilms' tumor 1 (WT1) antigen is highly expressed in various malignancies (8), including pancreatic cancer (8,9). Therefore, WT1 has been used as one of the targets of immunotherapy for pancreatic cancer (1, 7). For advanced pancreatic cancer, a WT1-peptide vaccine and WT1-peptide pulsed-dendritic cell (WT1-DC) vaccine have already been used in combination with chemotherapy agents, such as gemcitabine and S-1, in multiple studies, and its safety has been verified (10-16). Additionally, its clinical effects have been reported (11)(12)(13). Positive findings, such as WT1-specific delayed-type hypersensitivity after administration of the WT1-DC vaccine, reduced neutrophil/lymphocyte ratio in peripheral blood before or after administration, increased expression of CD83/human leukocyte antigen (HLA)-DR on DCs after administration, and no increase in interleukin-6 levels in peripheral blood after administration, have been reported as prognostic factors (13,15,16 (11,12).For patients diagnosed with primary pancreatic cancer, resection is the most important treatment, and implementation of postoperative chemotherapy can improve prognosis. In a recent report, the administration of S-1 alone was shown to be superior to that of gemcitabine for pancreatic cancer after resection (25). However, recurrence after surgery remains a serious problem. Therefore, the use of immunotherapy in combination with standard chemotherapy in the early phase can be considered as a strategy for the prevention of the recurrence of pancreatic cancer. Thus, in this study, we examined the safety of WT1-DC vaccine and acquisition of WT1-specific CTLs after administration of the vaccine with OK-432 as an adjuvant combined with chemotherapy (mainly S-1) in patients with surgically resected pancreatic cancer. Materials and MethodsPatient selection. Between August 2013 and March 2016, patients with pancreatic cancer were consecutively enrolled in this study. During this period, patients with several types of cancer received the WT1-DC vaccine at the Center for Advanced Cell Therapy in Shinshu University Hospital (26). We selected those with pancreatic cancer who underwent resection after initial diagnosis and then received chemotherapy. We excluded patients who received chemotherapy before surgery. Other eligibility criteria have been previously described (27)....

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Section: Methodsmentioning

confidence: 99%

WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study

Yanagisawa

Koizumi

Koya

et al. 2018

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“…The revised IFN-DC protocol has been demonstrated in research development to be a superior protocol for manufacturing DC vaccines. Compared with IL-4 DCs, IFN-DCs generated from human monocytes using GM-CSF and interferon (IFN)-α can induce differentiation in a shorter period of time [ 16 ]. Furthermore, compared with IL-4 DCs, IFN-DCs have been reported to be more capable of cross-presenting antigens to CD8 + T cells via major histocompatibility complex class I molecules after processing them into peptides [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Interferon-α-Induced Dendritic Cells Generated with Human Platelet Lysate Exhibit Elevated Antigen Presenting Ability to Cytotoxic T Lymphocytes

et al. 2020

Self Cite

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Given the recent advancements of immune checkpoint inhibitors, there is considerable interest in cancer immunotherapy provided through dendritic cell (DC)-based vaccination. Although many studies have been conducted to determine the potency of DC vaccines against cancer, the clinical outcomes are not yet optimal, and further improvement is necessary. In this study, we evaluated the potential ability of human platelet lysate (HPL) to produce interferon-α-induced DCs (IFN-DCs). In the presence of HPL, IFN-DCs (HPL-IFN-DCs) displayed high viability, yield, and purity. Furthermore, HPL-IFN-DCs displayed increased CD14, CD56, and CCR7 expressions compared with IFN-DCs produced without HPL; HPL-IFN-DCs induced an extremely higher number of antigen-specific cytotoxic T lymphocytes (CTLs) than IFN-DCs, which was evaluated with a human leukocyte antigen (HLA)-restricted melanoma antigen recognized by T cells 1 (MART-1) peptide. Additionally, the endocytic and proteolytic activities of HPL-IFN-DCs were increased. Cytokine production of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α was also elevated in HPL-IFN-DCs, which may account for the enhanced CTL, endocytic, and proteolytic activities. Our findings suggest that ex-vivo-generated HPL-IFN-DCs are a novel monocyte-derived type of DC with high endocytic and proteolytic activities, thus highlighting a unique strategy for DC-based immunotherapies.

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“…The latter pathway involves the expression of cytotoxic molecules belonging to the tumor necrosis factor family (TNFα, FasL, TRAIL, etc.) on the DC surface, which trigger target tumor cell death by binding to relevant receptors [3,5,8,9]. Nevertheless, killer function of DCs is poorly understood, thus raising many questions regarding its role in antitumor immune responses.…”

Section: Introductionmentioning

confidence: 99%

“…DCs differentiated in the presence of IFNα (IFN-DCs) represent a unique DC population, which differ from IL-4-DCs in possessing a more pronounced antigen-presenting ability, higher migration activity, and a more stable phenotype [13][14][15][16]. In addition, IFN-DCs exhibit cytotoxic activity against various tumor cell lines, express a wide range of cytotoxic ligands (TNFα, TRAIL, FasL, perforin), and also secrete granzyme B, which is barely produced by IL-4-DCs [5,9].…”

Section: Introductionmentioning

confidence: 99%

Defective Regulation of Membrane TNFα Expression in Dendritic Cells of Glioblastoma Patients Leads to the Impairment of Cytotoxic Activity against Autologous Tumor Cells

Тыринова

Леплина

Мишинов

et al. 2020

IJMS

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Besides an antigen-presenting function and ability to induce antitumor immune responses, dendritic cells (DCs) possess a direct tumoricidal activity. We previously reported that monocyte-derived IFNα-induced DCs (IFN-DCs) of glioblastoma multiforme patients express low levels of membrane TNFα molecule (mTNFα) and have impaired TNFα/TNF-R1-mediated cytotoxicity against immortalized tumor cell line HEp-2. However, whether the observed defect could affect killer activity of glioma patient DCs against autologous tumor cells remained unclear. Here, we show that donor IFN-DCs possess cytotoxic activity against glioblastoma cell lines derived from a primary tumor culture. Granule-mediated and TNFα/TNF-R1-dependent pathways were established as the main mechanisms underlying cytotoxic activity of IFN-DCs. Glioblastoma patient IFN-DCs showed lower cytotoxicity against autologous glioblastoma cells sensitive to TNFα/TNFR1-mediated lysis, which was associated with low TNFα mRNA expression and high TACE/ADAM-17 enzyme activity. Recombinant IL-2 (rIL-2) and human double-stranded DNA (dsDNA) increased 1.5-fold cytotoxic activity of patient IFN-DCs against autologous glioblastoma cells. dsDNA, but not rIL-2, enhanced the expression of TNFα mRNA and decreased expression and activity of TACE/ADAM-17 enzyme. In addition, dsDNA and rIL-2 stimulated the expression of perforin and granzyme B (in the presence of dsDNA), suggesting the possibility of enhancing DC cytotoxicity against autologous glioblastoma cells via various mechanisms.

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Interferon-α-inducible Dendritic Cells Matured with OK-432 Exhibit TRAIL and Fas Ligand Pathway-mediated Killer Activity

Cited by 14 publications

References 57 publications

WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study

WT1-pulsed Dendritic Cell Vaccine Combined with Chemotherapy for Resected Pancreatic Cancer in a Phase I Study

Interferon-α-Induced Dendritic Cells Generated with Human Platelet Lysate Exhibit Elevated Antigen Presenting Ability to Cytotoxic T Lymphocytes

Defective Regulation of Membrane TNFα Expression in Dendritic Cells of Glioblastoma Patients Leads to the Impairment of Cytotoxic Activity against Autologous Tumor Cells

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