Vella, Laura Ann
(2008)
Cyclin B1: Abnormal Self/Tumor Antigen.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
We previously identified the aberrantly expressed cell cycle regulator cyclin B1 as a tumor antigen that can elicit both humoral and cellular immune responses in cancer patients. While cyclin B1 is only transiently expressed in normal cells, cancers of many tissue origins constitutively overexpress the cell cyclin in the cytoplasm, which correlates with poorer patient prognosis. We propose that this tumor-specific overabundance and cytoplasmic location of cyclin B1 leads to the presentation of high—and therefore immunogenic—concentrations of cyclin B1 peptides to the immune system. Our studies focused on the source of immune responses against cyclin B1 and the significance of these immune responses in the setting of cancer. To study the significance of the anti-cyclin B1 immune response in human cancer, we tested plasma from patients with non-small cell lung cancer (NSCLC) for anti-cyclin B1 IgG and demonstrated that a longer overall survival in patients with stage IB NSCLC is correlated with high levels of anti-cyclin B1 IgG. We also demonstrated that cyclin B1-specific antibody and T cell responses exist in healthy individuals who have no history of cancer. Further, the cyclin B1-specific T cells in healthy individuals are antigen experienced and in both CD4+ and CD8+ T cell compartments. We then sought to determine the potential significance of a preexisting anti-cyclin B1 immune response in the setting of cyclin B1+ tumor development. Using both transplantable and spontaneous mouse models of cyclin B1+ tumors, we demonstrated that vaccination against cyclin B1 prior to the administration or spontaneous development of cyclin B1+ tumors inhibits tumor growth. Finally, given that viral infection has been shown to lead to overexpression of cyclin B1, we proposed that the anti-abnormal self protein, anti-tumor antigen immune responses we observed in healthy people were a result of a virus infection. The extension of that hypothesis is that infections with viruses can train the immune system to recognize abnormal expression of self proteins and therefore protect from cancers that abnormally express those proteins as well. We demonstrated that infection with ectromelia, a mouse pox virus, protects from tumor challenge.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
5 September 2008 |
| Date Type: |
Completion |
| Defense Date: |
21 August 2008 |
| Approval Date: |
5 September 2008 |
| Submission Date: |
5 September 2008 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
autoantigen; cancer immunology; DNA vaccines; human immunology; tumor immunology |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-09052008-115532/, etd-09052008-115532 |
| Date Deposited: |
10 Nov 2011 20:01 |
| Last Modified: |
19 Dec 2016 14:37 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9331 |
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