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Integration of HSP90 inhibition in combinational immunotherapies targeting receptor tyrosine kinase EphA2

Rao, Aparna (2012) Integration of HSP90 inhibition in combinational immunotherapies targeting receptor tyrosine kinase EphA2. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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Status: Unpublished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:
CreatorsEmailPitt UsernameORCID
Rao, Aparnaapr15@pitt.eduAPR15
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairStorkus, Walterstorkuswj@upmc.eduSTORKUSW
Committee MemberBinder, Robertrjb42@pitt.eduRJB42
Committee MemberBrodsky, Jeffreyjbrodsky@pitt.eduJBRODSKY
Committee MemberFerris, Robertferrrl@upmc.edu
Committee MemberFerrone, Soldanoferrones@upmc.edu
Committee MemberWhiteside, Theresawhitesidetl@upmc.eduTLN7
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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