Influence of organ site and tumor cell type on MUC1-specific tumor immunity.
TL;DR: It is shown that it is more difficult to produce immune responses to tumors growing at the pancreatic site than the s.c.C.Tg mice, and immune responses evoked by presentation of MUC1 in wild-type mice were effective in rejecting tumor cells in the pancreas of both wild- type and M UC1.
Abstract: We investigated the influence of organ-specific parameters on tolerance and immunity to human MUC1. C57Bl/6 mice (wild-type) and C57Bl/6 transgenic for MUC1 (MUC1.Tg) were challenged in the pancreas with Panc02-MUC1, a C57Bl/6-syngeneic pancreatic cancer cell line expressing human MUC1. Wild-type mice produced immune responses to MUC1 when presented on tumor cells growing in the pancreas; however, the responses to tumors in the pancreas were less effective than responses produced by tumor challenge at the s.c. site. Tumor immunity specific for MUC1 was produced in wild-type mice by two different procedures: (i) s.c. immunization of wild-type mice with a low dose of Panc02-MUC1 or (ii) adoptive transfer of spleen and lymph node cells harvested from wild-type mice previously immunized s.c. with Panc02-MUC1. This demonstrates that immune responses to MUC1 presented at the s.c. site can be detected and adoptively transferred. MUC1.Tg mice were immunologically tolerant to MUC1; however, some immunological protection against orthotopic challenge with Panc02-MUC1 was conferred by adoptive transfer of CD4+ and CD8+ T cells from wild-type mice. These results show that it is more difficult to produce immune responses to tumors growing at the pancreatic site than the s.c. site. Panc02-MUC1 cells growing in the pancreas were accessible to the immune system, and immune responses evoked by s.c. presentation of this molecule in wild-type mice were effective in rejecting tumor cells in the pancreas of both wild-type and MUC1.Tg mice. No effective anti-tumor immune responses against MUC1 were produced in MUC1.Tg mice.
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11 Jul 2003TL;DR: In this paper, a MUC1 cytoplasmic tail peptide or portion thereof is used for inducing an immune response to MUC 1-expressing tumor cells and thus for preventing or treating cancer.
Abstract: The present invention relates to a MUC1 cytoplasmic tail peptide or portion thereof. These peptides are useful for inducing an immune response to MUC1-expressing tumor cells and thus for preventing or treating cancer.
16 citations
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TL;DR: B16.MUC1 immunity clearly demonstrate that different effector cells and cytolytic mechanisms are required to eliminate MUC1-expressing tumors derived from different organ sites, and provide insight into the immune components required to eliminated tumors expressing the same antigen butderived from different tissues.
Abstract: Previous studies have indicated that different effector cells are required to eliminate MUC1-expressing tumors derived from different organ sites and that different vaccine strategies may be necessary to generate these two different MUC1-specific immune responses. In this study, we characterized molecular components that are required to produce immune responses that eliminate Panc02.MUC1 tumors in vivo by utilizing mice genetically deficient in molecules related to immunity. A parallel study has been reported for a B16.MUC1 tumor model. We confirmed that a CD8+ effector cell was required to eliminate MUC1-expressing Panc02 tumors, and demonstrated that T cells expressing TCR-α/β and co-stimulation through CD28 and CD40:CD40L interactions played critical roles during the initiation of the anti-Panc02.MUC1 immune response. TCR-α/β+ cells were required to eliminate Panc02.MUC1 tumors, while TCR-γ/δ+ cells played a suppressive non-MUC1-specific role in anti-Panc02 tumor immunity. Type 1 cytokine interferon-gamma (IFN-γ), but not interleukin-12 (IL-12), was essential for eliminating MUC1-expressing tumors, while neither IL-4 nor IL-10 (type 2 cytokines) were required for tumor rejection. In vitro studies demonstrated that IFN-γ upregulated MHC class I, but not MHC class II, on Panc02.MUC1 tumor cells. Surprisingly, both perforin and FasL played unique roles during the effector phase of immunity to Panc02.MUC1, while lymphotoxin-α, but not TNFR-1, was required for immunity against Panc02.MUC1 tumors. The findings presented here and in parallel studies of B16.MUC1 immunity clearly demonstrate that different effector cells and cytolytic mechanisms are required to eliminate MUC1-expressing tumors derived from different organ sites, and provide insight into the immune components required to eliminate tumors expressing the same antigen but derived from different tissues.
16 citations
Cites background from "Influence of organ site and tumor c..."
...MUC1 tumor cells, and that CD4 cells contribute to tumor rejection when CD8 cells are present [41]....
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TL;DR: The increase in serum KL-6 levels appeared to be associated with the disruption of alveolar-capillary barrier after BLM-induced lung injury, and was positively correlated with BALF albumin levels, a representative marker for increased the alve SolarCapillary permeability.
12 citations
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TL;DR: It is possible that human tumors which secrete TGF-β1 may exhibit similar patho-physiological effects in the host depending on the anatomical site of the tumor.
Abstract: An ascitic lymphosarcoma (LS-A) of Swiss mice that regressed spontaneously on subcutaneous (s.c.) transplantation was investigated for the mechanism of its progressive growth and host mortality on intraperitoneal (i.p.) transplantation. In vitro studies indicated significant inhibition of LS-A proliferation seeded at higher cell density (>104/ml). Culture supernatants of LS-A caused bi-modal growth effects, the early supernatants (24 h) caused stimulation and the late (72 h) supernatants inhibited LS-A proliferation. The 72-h supernatants also suppressed T and B cell response to mitogens in a dose-dependent manner. Pan anti-transforming growth factor-β antibody abrogated the inhibitory effects of supernatants. The supernatants contained both latent as well as bio-active form of transforming growth factor-β1 (TGF-β1) as determined by ELISA. Mice bearing i.p. ascites tumor had elevated serum TGF-β1, hemoglobulinemia, splenic lymphopenia, impaired response of the T cells to mitogen and reduced expression of transferrin receptor (CD71) on the bone marrow cells. However, mice which rejected s.c. transplants, did not show significant changes in these parameters. Our studies indicated profound influence of site of tumor growth on tumor progression and host immune system mediated by tumor-derived TGF-β1. It is possible that human tumors which secrete TGF-β1 may exhibit similar patho-physiological effects in the host depending on the anatomical site of the tumor.
7 citations
Cites background from "Influence of organ site and tumor c..."
...Using orthotopic and ectopic transplantation of pancreatic tumor expressing human MUC1 transgene, the organ site was shown to be critical in the development of antiMUC1 immune response in mice [20]....
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TL;DR: It was found that immunotherapy alone increased Immunosuppressive cells in large tumors over time, whereas the anti-angiogenic therapy contained in the 4-in-1 strategy alleviated immunosuppression and made tumors vulnerable to immunotherapy, thus resulting in a synergistic antitumor effect.
3 citations
Cites background from "Influence of organ site and tumor c..."
...The local environment in different organs may influence the properties of tumors growing at those sites [30,31]....
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References
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TL;DR: The results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines and the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone.
Abstract: To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.
2,844 citations
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TL;DR: Detailed studies performed with one of the cytotoxic T-cell lines from pancreatic cancer patients show that it recognizes a specific antigen, a large and heavily glycosylated mucin molecule, expressed on pancreatic and breast tumors and tumor cell lines.
Abstract: We have previously reported the establishment of cytotoxic T-cell lines from pancreatic cancer patients, by continuously stimulating tumor-draining lymph node cells with allogeneic pancreatic tumor cell lines. After the preliminary characterization of their phenotype and tumor specificity, detailed studies performed with one of the cell lines, W.D., show that it recognizes a specific antigen, a large and heavily glycosylated mucin molecule, expressed on pancreatic and breast tumors and tumor cell lines. Although this recognition appears major histocompatibility complex (MHC)-unrestricted, the antigen receptor used by the cytotoxic T cell is the alpha/beta heterodimer, typically found on MHC-restricted T cells. The target antigen is atypical, however, in its ability to directly bind and activate the T cells in the absence of self MHC, presumably by abundant and regularly repeated antigenic epitopes. These findings are important because they demonstrate a specific T-cell response against a human tumor-associated antigen. In addition to pancreatic and breast tumors, various mucin molecules are known to be produced by other tumors of epithelial cell origin and could be expected to stimulate similar T-cell-mediated immune responses.
480 citations
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TL;DR: This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
444 citations
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TL;DR: Paracrine delivery of cytokines can be considered as a new type of adjuvant in the design of vaccines for cancer as well as microbial infections.
Abstract: Advances in our understanding of the molecular events of antigen recogni tion by T cells and T cell activation are opening up new approaches to cancer immunotherapy. The identification and cloning of cytokines provide one impor tant set of tools for manipulating immunologic responses. For cancer therapy, cytokines such as interleukin-2 have been administered systemically. However, systemic administration of cytokines ignores the paracrine nature of their ac tion. Recently, an alternative approach has been explored that produces high concentrations of cytokines local to the tumor cells. This is achieved either by transduction of the tumor cells the cytokine gene or by mixture of the tumor cells with cytokine containing biodegradable polymer microspheres. Under these circ umstances, the locally released cytokine produces a strong local inflammatory response specific to the particular cytokine. In some cases, a potent tumor-specific T cell response results, capable of mediating regression of systemi c tumor de posits. This paracrine delivery of cytokines can therefore be considered as a new type of adjuvant in the design of vaccines for cancer as well as microbial infections.
409 citations
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TL;DR: The data suggest that the highly repetitive nature of the mucin allows cross-linking of the T-cell receptor on mucin-specific T-cells and therefore accounts for the lack of MHC restriction seen in the tumor-reactive CTLs of patients with breast adenocarcinoma.
Abstract: A population of tumor-reactive cytotoxic T-cells can be propagated from tumor-draining lymph nodes of patients with breast adenocarcinoma. These T-cells specifically recognize breast and pancreatic tumor cells in a major histocompatibility complex (MHC)-unrestricted fashion but not other tumors of epithelial origin or the natural killer target K562. The tumor-specific but MHC-unrestricted lytic activity of these cytotoxic T-lymphocytes (CTLs) is mediated through the alpha/beta T-cell receptor. The molecule recognized by these CTLs is ductal epithelial mucin produced by breast and pancreatic adenocarcinomas. The protein core of the mucin consists of multiple tandem repeats of a 20-amino acid sequence. Antibody SM3, directed against a determinant on the mucin protein core preferentially expressed on malignant cells is able to significantly inhibit lysis of tumor cells by the CTL, while other antibodies binding to different core epitopes are not. Normal breast epithelial lines, which also express mucin but not the SM3 epitope, are not lysed by these tumor-reactive CTLs or act as cold target inhibitors of lysis of tumor lines. The data suggest that the highly repetitive nature of the mucin allows cross-linking of the T-cell receptor on mucin-specific T-cells and therefore accounts for the lack of MHC restriction seen in this system. They further suggest that the mucin core epitope recognized on tumor cells is not expressed on normal epithelial cells in a manner that can be recognized by tumor-reactive CTLs. These findings support the role of mucins as important tumor-associated antigens mediating the cellular response to certain human cancers and suggest that epithelial mucin core sequences might form the basis for an effective vaccine to augment the antitumor immune response.
370 citations