title: Myxomaviral Anti-Inflammatory Serpin Reduces Myeloid-Derived Suppressor Cells and Human Pancreatic Cancer Cell Growth in Mice.
abstract: Modification of the tumor microenvironment by inflammatory cells represents a newly recognized driving force in cancer with critical roles in tumor invasion, growth, angiogenesis, and metastasis. Increased thrombolytic cascade serine proteases, specifically urokinase-type plasminogen activator and its receptor, correlate with inflammatory cell migration, pancreatic cancer growth, invasion and unfavorable outcomes. Inflammation in pancreatic cancer is linked with myeloid-derived suppressor cell (MDSC) activity and cancer progression. Myxomavirus is a complex DNA virus encoding highly potent immune modulators. Serp-1 and M-T7 are two such secreted anti-inflammatory myxomaviral proteins. Serp-1 inhibits uPA, plasmin and coagulation factor X while M-T7 inhibits C, CC, and CXC chemokines. We have explored the potential use of these viral proteins for treatment of a range of human cancer isolates engrafted in severe combined immunodeficient (SCID) mice. Engrafted tumors were treated with either Serp-1, neuroserpin, a related mammalian serpin that inhibits thrombolytic proteases, or M-T7. Serp-1 and neuroserpin inhibited growth of the pancreatic cancer cell line Hs766t (P=0.03 and P=0.01, respectively) at 4 weeks after implantation. Serp-1 also inhibited growth of a second pancreatic cancer cell line MIA PaCa-2 in mice (P=0.02). Growth of the human breast cancer line MDA231 was not inhibited by Serp-1. M-T7, in contrast, did not alter growth of any of the cancer cell lines tested after implant into SCID mice. Serpin inhibition of pancreatic tumor growth was associated with a significant decrease in splenocyte MDSC counts by flow cytometry (P=0.009), without detected change in other splenocyte subpopulations. Serp-1 and NSP treatment also significantly reduced macrophage infiltration in tumors (P=0.001). In summary two anti-inflammatory serpins reduced inflammatory macrophage invasion and pancreatic tumor cell growth, suggesting potential therapeutic efficacy.
authors: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: Donghang
authors: D
authors: Zheng
authors: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: Hao
authors: H
authors: Chen
authors: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: Mee Y
authors: MY
authors: Bartee
authors: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: Jennifer
authors: J
authors: Williams
authors: Department of Medicine, University of Florida, Gainesville, FL, USA.
authors: Jennifer A
authors: JA
authors: Davids
authors: University of Cambridge, Cambridge, UK.
authors: David A
authors: DA
authors: Lomas
authors: Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
authors: Grant
authors: G
authors: McFadden
authors: Department of Medicine, University of Florida, Gainesville, FL, USA ; Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, USA.
authors: Alexandra R
authors: AR
authors: Lucas
keywords: Myeloid-derived suppressor cell; Pancreatic cancer; Serp-1; Serpin; Tumor-associated macrophage