Effect of antisense TGF-beta transgene expression on the immunogenicity of EMT6 murine mammary carcinoma cells

Persistent Link:
http://hdl.handle.net/10150/289056
Title:
Effect of antisense TGF-beta transgene expression on the immunogenicity of EMT6 murine mammary carcinoma cells
Author:
Park, Julie Anna, 1964-
Issue Date:
1997
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Transforming growth factor-beta (TGF-β) is a multi-functional cytokine produced by many tumor cells that is known to potently inhibit immune cell functions. Secretion of TGF-β by malignant cells may therefore be a mechanism by which tumor cells escape destruction by tumor-specific T lymphocytes. If this is the case, prevention of TGF-β production by tumor cells could be expected to eliminate tumor-derived immunosuppression and enable the development of effective anti-tumor immune responses. To evaluate the role of tumor-derived TGF-β on tumor progression, production of this cytokine was interrupted by introducing a gene encoding antisense TGF-β1 into the EMT6 murine mammary tumor cell line using a retroviral vector (LasTGF-β1SN). EMT6 cells transduced with this vector (EMT6asTGF-β1) stably expressed the antisense gene and secreted 48% less TGF-β than did tumor cells transduced with the backbone vector alone (EMT6-Neo). Supernatant fluid recovered from tumor calls expressing the antisense TGF-β1 gene also exhibited a decreased capacity to suppress alloantigen-specific cytotoxic T cell responses in vitro. Furthermore, tumor growth in mice injected with EMT6asTGF-β1 tumor cells was inhibited compared to mice injected with control EMT6-Neo tumor cells. Immune cell involvement in the growth inhibition of the antisense TGF-β transduced tumors was suggested by the ability of EMT6asTGF-β tumors to grow unchecked in immunodeficient scid mice and by the finding that immunocompetent mice that rejected antisense TGF-β1-expressing tumors developed long term tumor immunity. These results demonstrate that expression of antisense TGF-β1 by transduced EMT6 cells decreases their tumorigenicity and that this approach of eliminating immune suppression is a potentially useful strategy to enhance antitumor responses.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Immunology.; Health Sciences, Oncology.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Microbiology and Immunology
Degree Grantor:
University of Arizona
Advisor:
Akporiaye, Emmanuel T.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleEffect of antisense TGF-beta transgene expression on the immunogenicity of EMT6 murine mammary carcinoma cellsen_US
dc.creatorPark, Julie Anna, 1964-en_US
dc.contributor.authorPark, Julie Anna, 1964-en_US
dc.date.issued1997en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractTransforming growth factor-beta (TGF-β) is a multi-functional cytokine produced by many tumor cells that is known to potently inhibit immune cell functions. Secretion of TGF-β by malignant cells may therefore be a mechanism by which tumor cells escape destruction by tumor-specific T lymphocytes. If this is the case, prevention of TGF-β production by tumor cells could be expected to eliminate tumor-derived immunosuppression and enable the development of effective anti-tumor immune responses. To evaluate the role of tumor-derived TGF-β on tumor progression, production of this cytokine was interrupted by introducing a gene encoding antisense TGF-β1 into the EMT6 murine mammary tumor cell line using a retroviral vector (LasTGF-β1SN). EMT6 cells transduced with this vector (EMT6asTGF-β1) stably expressed the antisense gene and secreted 48% less TGF-β than did tumor cells transduced with the backbone vector alone (EMT6-Neo). Supernatant fluid recovered from tumor calls expressing the antisense TGF-β1 gene also exhibited a decreased capacity to suppress alloantigen-specific cytotoxic T cell responses in vitro. Furthermore, tumor growth in mice injected with EMT6asTGF-β1 tumor cells was inhibited compared to mice injected with control EMT6-Neo tumor cells. Immune cell involvement in the growth inhibition of the antisense TGF-β transduced tumors was suggested by the ability of EMT6asTGF-β tumors to grow unchecked in immunodeficient scid mice and by the finding that immunocompetent mice that rejected antisense TGF-β1-expressing tumors developed long term tumor immunity. These results demonstrate that expression of antisense TGF-β1 by transduced EMT6 cells decreases their tumorigenicity and that this approach of eliminating immune suppression is a potentially useful strategy to enhance antitumor responses.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Immunology.en_US
dc.subjectHealth Sciences, Oncology.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineMicrobiology and Immunologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorAkporiaye, Emmanuel T.en_US
dc.identifier.proquest9729483en_US
dc.identifier.bibrecord.b34811989en_US
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