?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F21581%2F&rft.title=HMGB1%2C+RAGE%2C+and+the+Myeloid+Response+to+Pancreatic+Cancer&rft.creator=Vernon%2C+Philip+J&rft.description=%0D%0AWe+have+ablated+HMGB1+in+CD11c%2B+cells+(DCH+mice)+to+evaluate+the+role+of+DC+HMGB1+loss%2C+immunologically%2C+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%2C+as+well+as+promoting+cytosolic+autophagy+in+the+setting+of+stress.+When+released+extracellularly+following+necrosis+or+during+stress%2C+it+serves+as+a+damage+associated+molecular+pattern+(DAMP)+molecule.+DCH+mice+represent+a+novel+model+to+answer+several+questions.+First%2C+is+HMGB1+necessary+for+DC+function%3F+Second%2C+can+KO-DCs+confer+protection+as+therapeutic+vaccines+in+anti-tumor+models+of+PDAC%3F+Lastly%2C+how+is+carcinogenesis+affected+in+a+Kras-driven+model+of+pancreatic+neoplasia+(KC+mice)+in+the+presence+of+KO-DCs%3F+KO-DCs+to+be+less+responsive+to+maturational+stimuli%2C+have+inhibited+T+cell+stimulatory+capacity%2C+and+skew+na%C3%AFve+T+cells+towards+regulatory+phenotypes.+KO-DCs+fail+to+initiate+anti-tumor+immunity+in+multiple+tumor+vaccine+models+compared+to+controls.+Unexpectedly%2C+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%2C+we+next+examined+the+role+of+the+HMGB1+receptor%2C+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%2C+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%2C+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.++%0D%0A&rft.date=2014-05-13&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F21581%2F1%2FPhilip_Vernon_ETD_Version_3.pdf&rft.identifier=++Vernon%2C+Philip+J++(2014)+HMGB1%2C+RAGE%2C+and+the+Myeloid+Response+to+Pancreatic+Cancer.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++