Prevention of Spontaneous Breast Carcinoma by Prophylactic Vaccination with Dendritic/Tumor Fusion Cells
15 Feb 2003-Journal of Immunology (American Association of Immunologists)-Vol. 170, Iss: 4, pp 1980-1986
TL;DR: It is indicated that prophylactic vaccination with dendritic/tumor fusion cells confers sufficient antitumor immunity to counter the tumorigenesis of potent oncogenic products.
Abstract: Genetically modified mice with spontaneous development of mammary carcinoma provide a powerful tool to study the efficacy of tumor vaccines, since they mimic breast cancer development in humans. We used a transgenic murine model expressing polyomavirus middle T oncogene and mucin 1 tumor-associated Ag to determine the preventive effect of a dendritic/tumor fusion cell vaccine. The MMT (a transgenic murine model) mice developed mammary carcinoma between the ages of 65-108 days with 100% penetrance. No spontaneous CTL were detected. However, prophylactic vaccination of MMT mice with dendritic/tumor fusion cells induced polyclonal CTL activity against spontaneous mammary carcinoma cells and rendered 57-61% of the mice free of the disease at the end of experiment (180 days). Furthermore, the level of CTL activity was maintained with multiple vaccinations. The antitumor immunity induced by vaccination with dendritic/tumor fusion cells reacted differently to injected tumor cells and autochthonous tumor. Whereas the injected tumor cells were rejected, the autochthonous tumor evaded the attack and was allowed to grow. Collectively these results indicate that prophylactic vaccination with dendritic/tumor fusion cells confers sufficient antitumor immunity to counter the tumorigenesis of potent oncogenic products. The findings in the present study are highly relevant to cancers in humans.
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TL;DR: This review focuses on the three best-characterized cell surface mucins expressed in the respiratory tract: MUC1, MUC4, and MUC16.
Abstract: Cell surface mucins are large transmembrane glycoproteins involved in diverse functions ranging from shielding the airway epithelium against pathogenic infection to regulating cellular signaling and transcription. Although hampered by the relatively recent characterization of cell surface mucins and the difficulties inherent in working with molecules of their size, numerous studies have placed the tethered mucins in the thick of normal and diseased lung physiology. This review focuses on the three best-characterized cell surface mucins expressed in the respiratory tract: MUC1, MUC4, and MUC16.
669 citations
TL;DR: New mouse models that recapitulate significant features of human cancer progression show that vaccines can keep precancerous lesions under control and might eventually be the spearhead of effective and reliable ways to prevent cancer.
Abstract: Despite tremendous progress in basic and epidemiological research, effective prevention of most types of cancer is still lacking Vaccine use in cancer therapy remains a promising but difficult prospect However, new mouse models that recapitulate significant features of human cancer progression show that vaccines can keep precancerous lesions under control and might eventually be the spearhead of effective and reliable ways to prevent cancer
307 citations
Journal Article•
TL;DR: Data suggest that endogenous expression of MUC1 protein by M UC1 transgenic mice induces T-cell tolerance to stimulation by MUC2, and will facilitate the investigation of anti-MUC1 immunotherapy formulations.
Abstract: The human epithelial mucin, MUC1, is a large transmembrane glycoprotein that is expressed on most simple epithelia. It is overexpressed and aberrantly glycosylated on many human epithelial tumors, including more than 90% of human breast cancers. MUC1 is of interest as an immunotherapy target because patients with breast, ovarian, and pancreatic cancers have T lymphocytes in their tumor-draining lymph nodes that can be induced to recognize and lyse MUC1-expressing tumor cells. We have produced a transgenic mouse model that expresses the human MUC1 molecule on an inbred C57Bl/6 background to investigate the effect of endogenous expression of MUC1 on the ability of mice to generate antitumor immunity to MUC1-expressing tumors. Transgenic mice expressed the human transgene in a pattern and level consistent with that observed in humans. Transgenic mice were tolerant to stimulation by MUC1 as evidenced by the ability of MUC1-expressing tumor cells to grow in these mice, whereas MUC1-expressing cells were eliminated from wild-type mice. Moreover, transgenic mice immunized with MUC1 peptides failed to exhibit immunoglobulin class switching to the IgG subtypes. These data suggest that endogenous expression of MUC1 protein by MUC1 transgenic mice induces T-cell tolerance to stimulation by MUC1. The transgenic mice will provide a useful model to investigate the mechanisms that regulate immunological tolerance to tumor antigens and will facilitate the investigation of anti-MUC1 immunotherapy formulations.
193 citations
TL;DR: A novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines.
Abstract: We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines.
135 citations
Cites background from "Prevention of Spontaneous Breast Ca..."
...This oncogene is active throughout all stages of mammary gland development, resulting in widespread transformation and production of multifocal mammary adenocarcinomas by 9–10 wk of age, which metastasize to the lungs and bone marrow by 20 wk (10, 43)....
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TL;DR: Transgenic mouse models in which tumors arise spontaneously have been developed for most cancers and additional improvements are needed so that more realistic models can be developed.
124 citations
References
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TL;DR: The Surveillance Research Program of the American Cancer Society's Department of Epidemiology and Surveillance Research reports its annual compilation of estimated cancer incidence, mortality, and survival data for the United States in the year 2000.
Abstract: The Surveillance Research Program of the American Cancer Society's Department of Epidemiology and Surveillance Research reports its annual compilation of estimated cancer incidence, mortality, and survival data for the United States in the year 2000. After 70 years of increases, the recorded number of total cancer deaths among men in the US declined for the first time from 1996 to 1997. This decrease in overall male mortality is the result of recent down-turns in lung and bronchus cancer deaths, prostate cancer deaths, and colon and rectum cancer deaths. Despite decreasing numbers of deaths from female breast cancer and colon and rectum cancer, mortality associated with lung and bronchus cancer among women continues to increase. Lung cancer is expected to account for 25% of all female cancer deaths in 2000. This report also includes a summary of global cancer mortality rates using data from the World Health Organization.
3,858 citations
TL;DR: The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II- negative precursors in marrow, and this feature should prove useful for future molecular and clinical studies of this otherwise trace cell type.
Abstract: Antigen-presenting, major histocompatibility complex (MHC) class II-rich dendritic cells are known to arise from bone marrow. However, marrow lacks mature dendritic cells, and substantial numbers of proliferating less-mature cells have yet to be identified. The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II-negative precursors in marrow. A key step is to remove the majority of nonadherent, newly formed granulocytes by gentle washes during the first 2-4 d of culture. This leaves behind proliferating clusters that are loosely attached to a more firmly adherent "stroma." At days 4-6 the clusters can be dislodged, isolated by 1-g sedimentation, and upon reculture, large numbers of dendritic cells are released. The latter are readily identified on the basis of their distinct cell shape, ultrastructure, and repertoire of antigens, as detected with a panel of monoclonal antibodies. The dendritic cells express high levels of MHC class II products and act as powerful accessory cells for initiating the mixed leukocyte reaction. Neither the clusters nor mature dendritic cells are generated if macrophage colony-stimulating factor rather than granulocyte/macrophage colony-stimulating factor (GM-CSF) is applied. Therefore, GM-CSF generates all three lineages of myeloid cells (granulocytes, macrophages, and dendritic cells). Since > 5 x 10(6) dendritic cells develop in 1 wk from precursors within the large hind limb bones of a single animal, marrow progenitors can act as a major source of dendritic cells. This feature should prove useful for future molecular and clinical studies of this otherwise trace cell type.
3,852 citations
"Prevention of Spontaneous Breast Ca..." refers methods in this paper
...DC were obtained from bone marrow culture of C57BL/6 mice as described previously (25)....
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TL;DR: Results suggest that middle T antigen acts as a potent oncogene in the mammary epithelium and that cells that express it possess an enhanced metastatic potential.
Abstract: The effect of mammary gland-specific expression of the polyomavirus middle T antigen was examined by establishing lines of transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/enhancer. By contrast to most transgenic strains carrying activated oncogenes, expression of polyomavirus middle T antigen resulted in the widespread transformation of the mammary epithelium and the rapid production of multifocal mammary adenocarcinomas. Interestingly, the majority of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. Taken together, these results suggest that middle T antigen acts as a potent oncogene in the mammary epithelium and that cells that express it possess an enhanced metastatic potential.
1,536 citations
"Prevention of Spontaneous Breast Ca..." refers background in this paper
...The association with and activation of the tyrosine kinase activity of these signal transduction proteins by PyMT Ag promote cell growth and/or survival and result in widespread transformation of the mammary epithelia and rapid production of multifocal mammary adenocarcinomas in 100% of female mice (1, 13)....
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...Alternatively, stimulation by the oncogene product may be too powerful to be inhibited in the long term, since PyMT is a potent oncogene (1, 41)....
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...Gendler, unpublished observation) expresses the polyomavirus middle T (PyMT)(3) oncogene under the transcriptional control of the mouse mammary tumor virus promoter long terminal repeats (1) and the human mucin 1 (MUC1) in a tissue-specific fashion (2)....
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...The majority of the mice develop metastases in the lungs (1)....
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...The transgenic mice include 1) MT mice expressing polyomavirus middle T (PyMT) oncogene driven by the mouse mammary tumor virus long terminal repeat and developing spontaneous mammary carcinoma (1), 2) MUC1 transgenic mice (MUC1....
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TL;DR: Results suggest that B7 expression renders tumor cells capable of effective antigen presentation, leading to their eradication in vivo.
Abstract: A variety of tumors are potentially immunogenic but do not stimulate an effective anti-tumor immune response in vivo. Tumors may be capable of delivering antigen-specific signals to T cells, but may not deliver the costimulatory signals necessary for full activation of T cells. Expression of the costimulatory ligand B7 on melanoma cells was found to induce the rejection of a murine melanoma in vivo. This rejection was mediated by CD8+ T cells; CD4+ T cells were not required. These results suggest that B7 expression renders tumor cells capable of effective antigen presentation, leading to their eradication in vivo.
1,269 citations
"Prevention of Spontaneous Breast Ca..." refers background in this paper
...Tumor cells are known to evade the immune system by down-regulation of tumor Ag/MHC molecules (35, 36), by Ag presentation in the absence of costimulatory molecules (37, 38), or by the development of tolerance and/or anergy of T cells (39)....
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TL;DR: The results show that the fusion cells stimulate naive T cells in the primary mixed lymphocyte reaction (MLR) and induce MC38 tumor-specific CTLs in vivo and induces rejection of established metastases.
Abstract: Dendritic cells (DCs) are potent antigen-presenting cells that prime naive cytotoxic T-cells (CTLs). In this study, we have fused DCs with MC38 carcinoma cells. The fusion cells were positive for major histocompatibility (MHC) class I and II, costimulating molecules and intercellular cell adhesion molecule-1 (ICAM-1). The results show that the fusion cells stimulate naive T cells in the primary mixed lymphocyte reaction (MLR) and induce MC38 tumor-specific CTLs in vivo. Antibody-mediated depletion experiments demonstrate that induction of CD4+ and CD8+ CTLs protects against challenge with tumor cells. We also show that immunization with the fusion cells induces rejection of established metastases. These findings represent the first demonstration that fusions of DCs and tumor cells can be used in the treatment of cancer.
603 citations
"Prevention of Spontaneous Breast Ca..." refers background in this paper
...Previous data indicate that immunization of mice with FC/MUC1 induces antitumor immune responses that provide protection against the challenge of MUC1-positive tumor cells (26, 29)....
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