Persistent Link:
http://hdl.handle.net/10150/280040
Title:
Immunological consequences of apoptosis in a tumor system
Author:
Feng, Hanping
Issue Date:
2002
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:
Cell lines genetically deficient in caspase-8 have been shown to be resistant to Fas-induced apoptosis, indicating that this pathway may be caspase-8-dependent. Some reports, however, have shown that Fas can induce cell death independent of caspase-8. In this study, we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway in the BCR-ABL positive leukemia cell line, 12B1-D1. Our data suggest that there is a novel, caspase-8-independent, Z-VAD-FMK inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly. In attempting to develop effective anti-cancer immunotherapies the relative ability of apoptotic cells to induce an immune response remains an important but controversial consideration. Apoptotic tumor cells can theoretically be a suitable antigen source for stimulation of anti-tumor responses. HSPs can act as danger signals to the immune system. We, therefore, hypothesize that the immunogenicity of apoptotic cell may be enhanced if endogenous HSP expression is induced, or an exogenous source of HSPs is present. To induce endogenous HSPs expression, the engineered 12B1-D1 cells are heat stressed before the induction of apoptosis by AP20187. These stressed apoptotic 12B1-D1 cells express HSP60 and HSP72 on their surface. Vaccination of mice with stressed apoptotic 12B1-D1 cells, but not non-stressed ones, elicits a potent cell-mediated anti-tumor immunity that significantly retards tumor progression. We have further demonstrated that, stressed apoptotic cells had higher abilities to upregulate the co-stimulatory molecules on the surface of DC, to stimulate DC to secrete proinflammatory cytokines, and to enhance their immunostimulatory functions. We further explored whether the immunogenicity of non-stressed apoptotic cell can be enhanced if an exogenous source of HSPs is present at the vaccination site. We used liver derived chaperone proteins co-injected with non-stressed apoptotic tumors to mice. Reproducibly this resulted in the generation of a durable and specific T-cell-mediated anti-tumor immunity. In summary, we have demonstrated that apoptotic tumor cells can be either immunogenic or non-immunogenic and DC may play a key role in determining the immunological consequences of apoptotic tumor cells. We have further demonstrated that normal tissue (liver) MCC may function as a danger signal for the immune system. These may provide new insights for combining immunotherapy with conventional therapies for treatment of cancers.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Microbiology.; 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:
Katsanis, Emmanuel

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleImmunological consequences of apoptosis in a tumor systemen_US
dc.creatorFeng, Hanpingen_US
dc.contributor.authorFeng, Hanpingen_US
dc.date.issued2002en_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.abstractCell lines genetically deficient in caspase-8 have been shown to be resistant to Fas-induced apoptosis, indicating that this pathway may be caspase-8-dependent. Some reports, however, have shown that Fas can induce cell death independent of caspase-8. In this study, we provide evidence for an alternative, caspase-8-independent, Fas death domain-mediated apoptotic pathway in the BCR-ABL positive leukemia cell line, 12B1-D1. Our data suggest that there is a novel, caspase-8-independent, Z-VAD-FMK inhibitable, apoptotic pathway in 12B1-D1 cells that targets mitochondria directly. In attempting to develop effective anti-cancer immunotherapies the relative ability of apoptotic cells to induce an immune response remains an important but controversial consideration. Apoptotic tumor cells can theoretically be a suitable antigen source for stimulation of anti-tumor responses. HSPs can act as danger signals to the immune system. We, therefore, hypothesize that the immunogenicity of apoptotic cell may be enhanced if endogenous HSP expression is induced, or an exogenous source of HSPs is present. To induce endogenous HSPs expression, the engineered 12B1-D1 cells are heat stressed before the induction of apoptosis by AP20187. These stressed apoptotic 12B1-D1 cells express HSP60 and HSP72 on their surface. Vaccination of mice with stressed apoptotic 12B1-D1 cells, but not non-stressed ones, elicits a potent cell-mediated anti-tumor immunity that significantly retards tumor progression. We have further demonstrated that, stressed apoptotic cells had higher abilities to upregulate the co-stimulatory molecules on the surface of DC, to stimulate DC to secrete proinflammatory cytokines, and to enhance their immunostimulatory functions. We further explored whether the immunogenicity of non-stressed apoptotic cell can be enhanced if an exogenous source of HSPs is present at the vaccination site. We used liver derived chaperone proteins co-injected with non-stressed apoptotic tumors to mice. Reproducibly this resulted in the generation of a durable and specific T-cell-mediated anti-tumor immunity. In summary, we have demonstrated that apoptotic tumor cells can be either immunogenic or non-immunogenic and DC may play a key role in determining the immunological consequences of apoptotic tumor cells. We have further demonstrated that normal tissue (liver) MCC may function as a danger signal for the immune system. These may provide new insights for combining immunotherapy with conventional therapies for treatment of cancers.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Microbiology.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.advisorKatsanis, Emmanuelen_US
dc.identifier.proquest3053908en_US
dc.identifier.bibrecord.b42819635en_US
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