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Engaging the Immune Response to Normalize the Tumor Microenvironment

Sabins, Nina and Storkus, Walter (2013) Engaging the Immune Response to Normalize the Tumor Microenvironment. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Solid tumors exist as heterogeneous populations comprised not only of malignant cells, but various other cell types, including cells that make up the vasculature, that can strongly influence tumorgenicity. Many forms of solid cancers are highly vascularized due to dysregulated angiogenesis. The tumor vasculature is classified by leaky, chaotic blood vessels consisting of several components including vascular endothelial cells and pericytes, as well vascular progenitors, resulting in vascular permeability and high interstitial pressure. As a result, the tumor vasculature limits the access of immune effector cells to the tumor, and may in part be responsible for the modest success observed in many current anti-cancer immunotherapies. Current first-line therapeutics in the advanced stage disease setting include anti-angiogenic small molecule drugs that have yielded high objective clinical response rates, however these responses tend to be transient in nature, with most patients becoming drug-refractory. Anti-tumor vasculature vaccines may promote the reconditioning of the tumor microenvironment by coordinately promoting a pro-inflammatory environment and the specific immune targeting of tumor-associated stromal cell populations that contribute to vasculature destabilization. Implementing a vaccine with these therapeutic effects is a promising treatment option that may extend disease-free intervals and overall patient survival. I show that vaccines specifically targeting tumor vasculature populations can “normalize” the tumor microenvironment, as shown by upregulation of proinflammatory molecules within the tumor as well as vascular remodeling promoting enhanced recruitment of CD8+ T cells, resulting in superior anti-tumor efficacy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Sabins, Ninanic25@pitt.eduNIC25
Storkus, Walterstorkuswj@upmc.eduSTORKUSW
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorStorkus, Walter Jstorkuswj@upmc.eduSTORKUSW
Committee MemberFinn, Olivera Jojfinn@pitt.eduOJFINN
Committee MemberButterfield, Lisa Hbutterfieldl@upmc.eduLHB3
Committee MemberLarregina, Adriana Tadrianal@pitt.eduADRIANAL
Committee MemberStolz, Donna Bdstolz@pitt.eduDSTOLZ
Committee MemberOkada,
Date: 29 August 2013
Date Type: Publication
Defense Date: 19 July 2013
Approval Date: 29 August 2013
Submission Date: 9 August 2013
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 167
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: cancer, vaccine, lentivirus, vasculature, dendritic cell
Date Deposited: 29 Aug 2013 19:57
Last Modified: 19 Dec 2016 14:41


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