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Alfa-mannosidase inhibitor effect, Swainsonina, on the phenotype of tumor associated macrophages

Grant number: 16/16149-1
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): November 01, 2016
Effective date (End): November 30, 2018
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Ana Paula Lepique
Grantee:Marcella Cipelli
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Infection with human papillomavirus (HPV) is the main etiologic factor of cervical cancer, as well as other anogenital and oropharyngeal tumors. Despite our body being able to recognize and eliminate these viruses, HPV have several escape mechanisms of the immune response, reaching remain decades in some infected individuals. In such cases, cells infected with HPV purchase: resistance to apoptosis, independent of mitogenic signals, the potential for unlimited proliferation, angiogenesis, and evasion of the immune response to the development of an invasive carcinoma. During this process, the immune system plays an important role, but not fully established. It is known, for example, the number of infiltrating macrophages increase in proportion to the degree of the lesion, with a maximum of cancer. Our laboratory and others have shown that tumor associated macrophages facilitate tumor growth. Swainsonine is an enzyme that specifically inhibits the enzyme alpha-mannosidase family, expressed by both tumor cells and by macrophages. Our laboratory identified this enzyme as a potential therapeutic target, using the methodology of "peptide phage display" with tumor lines derived from cervical cancer. Treatment of mice with partially Swainsonine inhibits tumor growth by promoting reduction of expression of arginase, an M2 type macrophage marker. In order to determine if inhibition of alpha-mannosidase has a direct effect on the phenotype of macrophages associated with tumors, this project will investigate the effect of treatment with Swainsonine on the phenotype of isolated tumor macrophages, and on their ability to activate T lymphocytes.