Myxomaviral anti-inflammatory serpin reduces myeloid-derived suppressor cells and human pancreatic cancer cell growth in mice

Donghang Zheng, Hao Chen, Mee Y. Bartee, Jennifer Williams, Jennifer A. Davids, David A. Lomas, Grant McFadden, Alexandra R. Lucas

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)291-299
Number of pages9
JournalJournal of Cancer Science and Therapy
Volume5
Issue number8
DOIs
StatePublished - Sep 30 2013

Keywords

  • Myeloid-derived suppressor cell
  • Pancreatic cancer
  • Serp-1
  • Serpin
  • Tumor-associated macrophage

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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