The Kinetics of In Vivo Priming of CD4 and CD8 T Cells by Dendritic/Tumor Fusion Cells in MUC1-Transgenic Mice

Koido, Shigeo; Tanaka, Yasuhiro; Chen, Dongshu; Küfe, Donald; Gong, Jianlin

doi:10.4049/jimmunol.168.5.2111

Cited by 63 publications

(49 citation statements)

References 47 publications

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“…Both OK-432 and HSPs are putative ligands of the TLR, stimulate DCs rapidly, and elicit a Th1-promoting phenotype (61,62), all of which are essential for exhibiting capacities to prime naive T cells and develop antitumor CTL responses. Our previous study, which found that depletion of CD4 ϩ T cells significantly impairs CTL induction by DCs/tumor FCs (11,41,63,64), indicates that efficient CTL generation requires the help of CD4 ϩ T cells. Our present study has shown that OK/HS-FCs are superior to other FC preparations for expanding the population of both CD4 ϩ and CD8 ϩ T cells that produce high levels of IFN-␥.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- γ at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+IFN-γ+CD8+ T cells and CD154+ IFN-γ+CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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“…The cytokine production patterns in this study reflect the polyclonal populations of activated T cells rather than the cytokine profile of an individual T cell. 24,41,42 The low level of IL-10 production did not influence the development of specific CTL responses induced by DC/CRCA fusion cells. It was shown that DCs were capable of stimulating T cells to produce IL-10 nonspecifically, and this pattern of production did not influence therapeutic responses.…”

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confidence: 99%

“…24,40 Both CD4 1 and CD8 1 T cells stimulated by DC/CRCA fusion cells produced IFN-g and were blocked by anti-MHC class I and/or class II MAb, suggesting antigen presentation by fusion cells through MHC class I and class II pathways. The activation of CD4 1 T cells by fusion cells is significant since they play an important role in the induction and maintenance of CTLs.…”

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confidence: 99%

“…23 In the fusion approach, multiple tumor antigens, including those known and unidentified, are processed endogenously and presented by MHC class I and II pathways in the context of costimulatory signals. 24 In animal studies, vaccination with fusions of murine tumor cells and syngeneic DCs resulted in the elimination of established lung metastasis. 23 Immunization of MUC1-transgenic mice with MUC1-positive fusion cells reversed immunologic unresponsiveness to MUC1 and induced immunity against MUC1-expressing tumors.…”

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Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells

et al. 2005

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Human metastatic colorectal carcinomas (CRCAs) express carcinoembryonic antigen (CEA) and/or MUC1 tumor-associated antigens as potential targets for the induction of active specific immunity. In the present study, freshly isolated metastatic CRCA cells were successfully fused with immature autologous human monocyte-derived dendritic cells (DCs). The created heterokaryons (DC/CRCA) coexpress the CRCA-derived CEA and MUC1 antigens and DC-derived MHC class II and costimulatory molecules. The fusion cells were functional in stimulating the proliferation of autologous T cells. In addition, both CD4 1 and CD81 T cells were activated by fusion cells, as demonstrated by the production of high levels of IFN-c. More importantly, coculture of fusion cells with patient-derived peripheral blood mononuclear cells (PBMCs) resulted in the induction of antigen-specific cytotoxic T lymphocytes (CTLs). CTLs were effective at lysis of not only autologous CRCA cells but also the CEA and/or MUC1-positive and HLA partially matched target cells. Antigen-specific CTL responses were confirmed by tetrameric analysis. Coculture of PBMCs with fusion cells resulted in increased frequency of CEAand MUC1-specific CTLs simultaneously. Taken together, these results indicate that freshly isolated human metastatic CRCA cells expressing the CEA and/or MUC1 may represent a potential partner for the creation of DC/tumor fusion cells targeting induction of antigen-specific CTL responses. Our report demonstrates the simultaneous induction of CRCA-specific CTL responses restricted by HLA-A2 and -A24. ' 2005 Wiley-Liss, Inc.Key words: dendritic cell; cytotoxic T lymphocyte; cytokine; MHC; tumor immunity CRCA is one of the most common malignancies and often metastasizes to the liver, lymph nodes and lung. At diagnosis, 15-20% of patients with CRCA have presented with metastatic liver disease. 1 Surgical resection is the treatment of choice for colorectal liver metastasis. However, tumor recurrence in the liver occurs in up to 60% of patients who undergo surgical resection.2 Therefore, therapy to prevent the recurrence of liver metastasis is needed. In this context, immunotherapy represents a potential approach for the prevention of recurrence of colorectal metastases. In support of the immunotherapy approach is the finding that CRCA cells overexpress the CEA, MUC1, Ep-CAM and Her-2/ neu antigens.3-8 CRCA cells also express mutated forms of the p53 and adenomatous polyposis coli 5,9 tumor-suppressor genes. In fact, there is increasing evidence that tumor-reactive and antigenspecific CTLs exist in patients with CRCA and have been expanded from tumor-infiltrating lymphocytes and PBMCs in CRCA patients. 7,8,10 These results indicate that active specific immunotherapy can be developed in patients with metastatic CRCA.DCs are potent professional APCs capable of priming naive T cells and inducing antigen-specific CTLs.11,12 DCs derive their potency from the expression of MHC class I and II, and costimulatory molecules that provide secondary signals for the acti...

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“…Most of these (Zitvogel et al, 1996;Ashley et al, 1997;Boczkowski et al, 2000;Irvine et al, 2000;Nair et al, 2000;Shimizu et al, 2001;Koido et al, 2002;Chen et al, 2003) have included control DC groups, whereas others have not (Soares et al, 2001). In reports that included a control group of unpulsed DCs, no significant protection was seen with these cells.…”

Section: Discussionmentioning

confidence: 99%

Immunisation with ‘naïve’ syngeneic dendritic cells protects mice from tumour challenge

et al. 2008

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Dendritic cells (DCs) 'pulsed' with an appropriate antigen may elicit an antitumour immune response in mouse models. However, while attempting to develop a DC immunotherapy protocol for the treatment of breast cancer based on the tumour-associated MUC1 glycoforms, we found that unpulsed DCs can affect tumour growth. Protection from RMA-MUC1 tumour challenge was achieved in C57Bl/6 MUC1 transgenic mice by immunising with syngeneic DCs pulsed with a MUC1 peptide. However, unpulsed DCs gave a similar level of protection, making it impossible to evaluate the effect of immunisation of mice with DCs pulsed with the specific peptide. Balb/C mice could also be protected from tumour challenge by immunisation with unpulsed DCs prior to challenge with murine mammary tumour cells (410.4) or these cells transfected with MUC1 (E3). Protection was achieved with as few as three injections of 50 000 naïve DCs per mouse per week, was not dependent on injection route, and was not specific to cell lines expressing human MUC1. However, the use of Rag2-knockout mice demonstrated that the adaptive immune response was required for tumour rejection. Injection of unpulsed DCs into mice bearing the E3 tumour slowed tumour growth. In vitro, production of IFN-g and IL-4 was increased in splenic cells isolated from mice immunised with DCs. Depleting CD4 T cells in vitro partially decreased cytokine production by splenocytes, but CD8 depletion had no effect. This paper shows that naïve syngeneic DCs may induce an antitumour immune response and has implications for DC immunotherapy preclinical and clinical trials.

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The Kinetics of In Vivo Priming of CD4 and CD8 T Cells by Dendritic/Tumor Fusion Cells in MUC1-Transgenic Mice

Cited by 63 publications

References 47 publications

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells

Immunisation with ‘naïve’ syngeneic dendritic cells protects mice from tumour challenge

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