Rao, Aparna
(2012)
Integration of HSP90 inhibition in combinational immunotherapies targeting receptor tyrosine kinase EphA2.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Limitations in CD8+ T cell recognition of tumor cells due to defects in their antigen processing machinery or the selection of variants expressing low or absent levels of cognate tumor antigens have been previously identified as impediments to effective cancer immunotherapy. Hence, treatment regimens that coordinately promote enhanced activation of anti-tumor CD8+ T cells, improved delivery of such effector cells into tumor sites, and augmented recognition of tumor or tumor-associated stromal cells by therapeutic CD8+ T cells, would be expected to yield greater clinical benefit. Using an MCA205 sarcoma model, I show that in vitro treatment of tumor cells with the HSP90 inhibitor 17-DMAG results in the transient (proteasome-dependent) degradation of the
HSP90 client protein EphA2 and the subsequent increased recognition of tumor cells by Type-1 anti-EphA2 CD8+ T cells. In vivo administration of 17-DMAG to tumor-bearing mice led to: i.) slowed tumor growth; ii.) enhanced/prolonged recognition of tumor cells by anti-EphA2 CD8+ T cells; iii.) reduced levels of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) in the tumor microenvironment (TME); and iv.) activation of tumor-associated vascular endothelial cells in association with elevated levels of Type-1 tumor infiltrating lymphocytes (TIL). When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG cotreatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease.
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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Unpublished |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: |
25 August 2012 |
| Date Type: |
Publication |
| Defense Date: |
18 July 2012 |
| Approval Date: |
25 August 2012 |
| Submission Date: |
12 August 2012 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
160 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
HSP90, immunotherapy, EphA2, 17-DMAG |
| Date Deposited: |
25 Aug 2012 15:39 |
| Last Modified: |
19 Dec 2016 14:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/13534 |
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