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HMGB1, RAGE, and the Myeloid Response to Pancreatic Cancer

Vernon, Philip J (2014) HMGB1, RAGE, and the Myeloid Response to Pancreatic Cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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We have ablated HMGB1 in CD11c+ cells (DCH mice) to evaluate the role of DC HMGB1 loss, immunologically, in vaccination strategies to tumor and in vivo in the setting of pancreatic carcinogenesis. HMGB1 is a chromatin-associated molecule regulating the response to several transcriptional factors, as well as promoting cytosolic autophagy in the setting of stress. When released extracellularly following necrosis or during stress, it serves as a damage associated molecular pattern (DAMP) molecule. DCH mice represent a novel model to answer several questions. First, is HMGB1 necessary for DC function? Second, can KO-DCs confer protection as therapeutic vaccines in anti-tumor models of PDAC? Lastly, how is carcinogenesis affected in a Kras-driven model of pancreatic neoplasia (KC mice) in the presence of KO-DCs? KO-DCs to be less responsive to maturational stimuli, have inhibited T cell stimulatory capacity, and skew naïve T cells towards regulatory phenotypes. KO-DCs fail to initiate anti-tumor immunity in multiple tumor vaccine models compared to controls. Unexpectedly, DCH mice inoculated with transplantable (pancreatic and colorectal cancer) tumor cells were significantly protected from tumor growth. BM transplants from DCH mice into KC mice resulted in significant inhibition of neoplasia and the associated inflammatory infiltrate. As DCs actively secrete HMGB1 during maturation, we next examined the role of the HMGB1 receptor, the receptor for advanced glycation-endproducts (RAGE) in the promotion of PDAC. We back-crossed RAGE-KO mice into the KC strain (KCR) and evaluated the role of RAGE in modulating the myeloid response to pancreatic carcinogenesis. We observed a significant delay in neoplasia in KCR mice and a correlation with a reduction in the accumulation of myeloid-derived suppressor cells (MDSCs). In the absence of RAGE and the development of malignant precursor lesions, non-immunosuppressive macrophages were detected in both the spleens and pancreata of KCR mice in lieu of MDSCs. These findings suggest a crucial role for myeloid cells in PDAC, including cell types conventionally thought to be inhibitory for tumor (DCs). Further investigation regarding the dynamic relationship between myeloid cells and PDAC is essential to for the success of immunotherapies in this disease.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Vernon, Philip Jpjv11@pitt.eduPJV11
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairLotze, Michael
Committee MemberKalinski, Pawelkalinskip@upmc.eduPAK5
Committee MemberSalter, Russell Drds@pitt.eduRDS
Committee MemberHackam, David J
Committee Memberbinder, robertrjb42@pitt.eduRJB42
Date: 13 May 2014
Date Type: Publication
Defense Date: 18 February 2014
Approval Date: 13 May 2014
Submission Date: 12 May 2014
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 142
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: damps, hmgb1, rage, pancreatic cancer, immunology
Date Deposited: 13 May 2014 11:43
Last Modified: 19 Dec 2016 14:41


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