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Journal ArticleDOI

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred

15 Sep 2000-Journal of Immunology (American Association of Immunologists)-Vol. 165, Iss: 6, pp 3451-3460
TL;DR: The MET mice appropriately mimic the human condition and are an excellent model with which to elucidate the native immune responses that develop during tumor progression and to develop effective antitumor vaccine strategies.
Abstract: Pancreatic cancer is a highly aggressive, treatment refractory cancer and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas overexpress altered forms of a tumor-specific Ag, mucin 1 (MUC1; an epithelial mucin glycoprotein), which is a potential target for immunotherapy. We have established a clinically relevant animal model for pancreatic cancer by developing a double transgenic mouse model (called MET) that expresses human MUC1 as self molecule and develops spontaneous tumors of the pancreas. These mice exhibit acinar cell dysplasia at birth, which progresses to microadenomas and acinar cell carcinomas. The tumors express large amounts of underglycosylated MUC1 similar to humans. Tumor-bearing MET mice develop low affinity MUC1-specific CTLs that have no effect on the spontaneously occurring pancreatic tumors in vivo. However, adoptive transfer of these CTLs was able to completely eradicate MUC1-expressing injectable tumors in MUC1 transgenic mice, and these mice developed long-term immunity. These CTLs were MHC class I restricted and recognized peptide epitopes in the immunodominant tandem repeat region of MUC1. The MET mice appropriately mimic the human condition and are an excellent model with which to elucidate the native immune responses that develop during tumor progression and to develop effective antitumor vaccine strategies.

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Citations
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Journal ArticleDOI
TL;DR: The common and the unique challenges to cancer vaccines and the progress that has been made in meeting them are addressed.
Abstract: Whether vaccines are designed to prepare the immune system for the encounter with a pathogen or with cancer, certain common challenges need to be faced, such as what antigen and what adjuvant to use, what type of immune response to generate and how to make it long lasting. Cancer, additionally, presents several unique hurdles. Cancer vaccines must overcome immune suppression exerted by the tumour, by previous therapy or by the effects of advanced age of the patient. If used for cancer prevention, vaccines must elicit effective long-term memory without the potential of causing autoimmunity. This article addresses the common and the unique challenges to cancer vaccines and the progress that has been made in meeting them. Considering how refractory cancer has been to standard therapy, efforts to achieve immune control of this disease are well justified.

615 citations

Journal ArticleDOI
Sandra J. Gendler1
TL;DR: Recent discoveries that suggest that MUC1 may be a multifunctional protein, located on the surfaces of cells as a sensor of the environment, poised to signal to the interior when things go awry are highlighted.
Abstract: MUC1 is a large, heavily glycosylated mucin expressed on the apical surfaces of most simple, secretory epithelia including the mammary gland, gastrointestinal, respiratory, urinary and reproductive tracts. Although MUC1 was thought to be an epithelial-specific protein, it is now known to be expressed on a variety of hematopoietic cells as well. Mucins function in protection and lubrication of epithelial surfaces. Transmembrane mucins, which contain cytoplasmic tail domains, appear to have additional functions through their abilities to interact with many proteins involved in signal transduction and cell adhesion. The goal of this review is to highlight recent discoveries that suggest that MUC1 may be a multifunctional protein, located on the surfaces of cells as a sensor of the environment, poised to signal to the interior when things go awry.

550 citations


Cites background from "Mice with Spontaneous Pancreatic Ca..."

  • ...The CTLs appeared to be effective in eradicating MUC1+ cells in the spontaneous pancreatic tumors, as immunohistochemical analysis of tumors taken at sacrifice showed little MUC1 reactivity, yet the tumors progressed, showing the need for multiple antigens in vaccine strategies (142)....

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  • ...human MUC1 at high levels and show underglycosylation typical of human adenocarcinomas (142)....

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  • ...The CTLs were specific for tumor MUC1 and, when adoptively transferred, killed MUC1-expressing tumor cells derived from mammary gland, pancreas, or melanomas (142)....

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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

Journal Article
TL;DR: This is the first study to show that T cells specific for pancreatic carcinoma cells can be generated in vitro by lysate-pulsed DCs and that the T-cell response can be enhanced by KLH, and can be applied to compare different strategies in the development of DC-based tumor vaccines.
Abstract: Dendritic cells (DCs) are potent antigen-presenting cells and play a pivotal role in T cell-mediated immunity. DCs have been shown to induce strong antitumor immune responses in vitro and in vivo, and their efficacy is being investigated in clinical trials. Compared with vaccination strategies directed against a single tumor antigen, tumor-cell lysate as the source of antigen offers the potential advantage of inducing a broad T-cell response against multiple known, as well as unknown, tumor-associated antigens expressed by the individual tumor. We used pancreatic carcinoma cell lines to develop an in vitro model for monitoring T-cell responses induced by lysate-pulsed DCs. Monocyte-derived DCs of HLA-A2(+) donors were pulsed with lysate generated from the HLA-A2(+) pancreatic carcinoma cell line Panc-1. In some experiments, the immunogenic protein keyhole limpet hemocyanin (KLH) was added to the lysate. Subsequently, the antigen-loaded DCs were activated with tumor necrosis factor-alpha and prostaglandin E(2). Autologous mononuclear cells were cocultured with DCs in the presence of low-dose interleukin (IL)-2 and IL-7 and were restimulated weekly with new DCs. High levels of IL-12 and IFN-gamma could be detected in the supernatants, indicating a T-helper type 1-type immune response. This cytokine profile was associated with the expression of the activation marker CD69 on both T helper and CTLs and with an antigen-induced proliferative T-cell response. After 4 weeks, CTL-mediated cytotoxicity was assessed. Tumor cell lysis was specific for Panc-1 tumor cells and was MHC class I-restricted. Cytokine secretion, CD69 expression of T cells, and antigen-induced T-cell proliferation correlated with the cytotoxic activity and were more pronounced when KLH was added to the lysate. This is the first study to show that T cells specific for pancreatic carcinoma cells can be generated in vitro by lysate-pulsed DCs and that the T-cell response can be enhanced by KLH. This in vitro model can be applied to compare different strategies in the development of DC-based tumor vaccines.

177 citations

References
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Journal ArticleDOI
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.

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TL;DR: This model indicates that self-reactive cytotoxic T cells may remain functionally unresponsive, owing to a lack of appropriate T cell activation, in so-called "T cell-mediated autoimmune diseases".

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Journal ArticleDOI
TL;DR: Functional studies are in progress both in vitro using cDNAs and cell lines and in vivo utilizing mutant mice in which a particular mucin gene has been inactivated or overexpressed to help determine whether the functions of mucins are restricted to protection and lubrication, or if they are involved in the adhesion of tumor cells to other cells or tissue components or in modulation of the immune system.
Abstract: The last seven years have been exciting in the world of mucin biology. Molecular analyses of mucin genes and deduced protein structures have provided insight into structural features of mucins and tools with which to examine expression, secretion, and glycosylation, thereby enabling a better understanding of the role of mucins in normal physiological processes and in disease. Functional studies are in progress both in vitro using cDNAs and cell lines and in vivo utilizing mutant mice in which a particular mucin gene has been inactivated or overexpressed. These studies should help determine whether the functions of mucins are restricted to protection and lubrication, or if they are involved in the adhesion of tumor cells to other cells or tissue components or in modulation of the immune system.

970 citations


"Mice with Spontaneous Pancreatic Ca..." refers background in this paper

  • ...The tandem repeats (TRs) serve as the scaffold for O-linked oligosaccharides that cover the polypeptide core (6)....

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Journal ArticleDOI
TL;DR: Altered HLA class I tumour phenotypes are analyzed in detail, indicating their potential relevance for implementation of immunotherapeutic protocols and strategies to overcome tumour escape mechanisms.

781 citations


"Mice with Spontaneous Pancreatic Ca..." refers background in this paper

  • ...Many reports have suggested that progressing tumors in cancer patients have elaborate means of escaping an apparently effective MHC class I-restricted immune response (45, 46)....

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Journal ArticleDOI
19 Apr 1991-Cell
TL;DR: The results indicate that a viral gene introduced as early as an animal's egg stage, incorporated into the germline, and expressed in islet cells does not produce tolerance when the host is exposed to the same virus later in life.

766 citations

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