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Tumor Blood Vessel-Associated Antigens as Targets for Cancer Immunotherapy

Fabian, Kellsye Paula (2017) Tumor Blood Vessel-Associated Antigens as Targets for Cancer Immunotherapy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The formation of neovessels is critical in the progression of solid tumors; hence, tumor angiogenesis is an attractive target for cancer therapy. A number of currently available anti-vascular and anti-angiogenic pharmacologic drugs have been shown to induce objective clinical responses, however, the therapeutic effects of these drugs are only transient, with patients developing drug-refractory disease in most cases. Therefore, the development of alternative therapies that durably regulate the tumor vasculature remains an unmet clinical need. Due to the dysregulated angiogenesis within growing tumors, tumor blood vessels are morphologically and functionally aberrant. The cells that make up the tumor vasculature, including pericytes and vascular endothelial cells, exhibit genomic and proteomic profiles that are markedly different than their counterparts in normal tissues. These differences affect the functions of the tumor-associated vascular cells, but they may also represent unique immunological targets for the development of interventional immunotherapies. In this thesis, I demonstrate that DLK1 and DLK2, which represent EGF-like protein antagonists of the Notch signaling pathway, are variably expressed in RENCA renal cell carcinoma-associated vascular pericytes. Vaccines that coordinately target both of these antigens result in the activation and recruitment of DLK1- and DLK2-specific, as well as, tumor-specific CD8+ tumor-infiltrating lymphocytes (TIL). The pro-inflammatory activity of vaccine-induced CD8+ TIL was associated with therapeutic reconditioning of the tumor stroma, and notably, the “normalization” of the tumor vasculature. Moreover, combination of immune checkpoint inhibitors (ICI) with the DLK1- and DLK2-targeted vaccine yielded a more effective therapy than either component modality, suggesting possible next-generation treatment options for patients with solid forms of cancer.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Fabian, Kellsye Paulakellsye@gmail.comklf730000-0002-0273-5647
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorStorkus, Walterstorkuswj@upmc.edu
Committee MemberButterfield, Lisabutterfieldl@upmc.edu
Committee MemberKalinski, PawelPawel.Kalinski@RoswellPark.org
Committee MemberLarregina, Adrianaadrianal@pitt.edu
Committee MemberMonga, Paulmongss@UPMC.EDU
Date: 26 June 2017
Date Type: Publication
Defense Date: 29 March 2017
Approval Date: 26 June 2017
Submission Date: 17 May 2017
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 161
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: tumor, cancer, immunotherapy, vaccine, DC, CD8+ T cells, vascular endothelial cells, pericytes, vascular normalization
Date Deposited: 26 Jun 2017 15:02
Last Modified: 26 Jun 2017 15:02
URI: http://d-scholarship.pitt.edu/id/eprint/32046

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