Swainsonine, an alpha-mannosidase inhibitor, may worsen cervical cancer progression through the increase in myeloid derived suppressor cells population

Autor(es):Mostrar menos -

Farina Silveira, Caio Raony ^[1] ; Cipelli, Marcella ^[1] ; Manzine, Carolina ^[1] ; Rabelo-Santos, Silvia Helena ^[2] ; Zeferino, Luiz Carlos ^[3] ; Rodriguez, Gretel Rodriguez ^[1] ; de Assis, Josiane Betim ^[1] ; Hebster, Suellen ^[4] ; Bernadinelli, Isabel ^[5] ; Laginha, Fabio ^[5] ; Boccardo, Enrique ^[4] ; Villa, Luisa Lina ^{[6, 7]} ; Termini, Lara ^[7] ; Lepique, Ana Paula ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Imunol, Inst Ciencias Biomed, Sao Paulo - Brazil

^[2] Univ Fed Goias, Inst Patol Trop & Saude Publ, Fac Farma, Goiania, Go - Brazil

^[3] Univ Estadual Campinas, Dept Ginecol & Obstet, Campinas, SP - Brazil

^[4] Univ Sao Paulo, Dept Microbiol, Inst Ciencias Biomed, Sao Paulo - Brazil

^[5] Hosp Perola Byington, Sao Paulo - Brazil

^[6] Inst Canc Estado Sao Paulo, Sao Paulo - Brazil

^[7] Univ Sao Paulo, Dept Radiol & Oncol, Fac Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 14, n. 3 MAR 6 2019.
• Citações Web of Science: 1

Resumo

Cervical cancer, caused by high oncogenic risk Human Papillomavirus (HPV) infection, continues to be a public health problem, mainly in developing countries. Using peptide phage display as a tool to identify potential molecular targets in HPV associated tumors, we identified a-mannosidase, among other enriched sequences. This enzyme is expressed in both tumor and inflammatory compartment of the tumor microenvironment. Several studies in experimental models have shown that its inhibition by swainsonine (SW) led to inhibition of tumor growth and metastasis directly and indirectly, through activation of macrophages and NK cells, promoting anti-tumor activity. Therefore, the aim of this work was to test if swainsonine treatment could modulate anti-tumor immune responses and therefore interfere in HPV associated tumor growth. Validation of our biopanning results showed that cervical tumors, both tumor cells and leukocytes, expressed a-mannosidase. Ex vivo experiments with tumor associated macrophages showed that SW could partially modulate macrophage phenotype, decreasing CCL2 secretion and impairing IL-10 and IL-6 upregulation, which prompted us to proceed to in vivo tests. However, in vivo, SW treatment increased tumor growth. Investigation of the mechanisms leading to this result showed that SW treatment significantly induced the accumulation of myeloid derived suppressor cells in the spleen of tumor bearing mice, which inhibited T cell activation. Our results suggested that SW contributes to cervical cancer progression by favoring proliferation and accumulation of myeloid cells in the spleen, thus exacerbating these tumors systemic effects on the immune system, therefore facilitating tumor growth. (AU)

• Processo FAPESP: 14/19326-6 - Microambiente tumoral, inflamação e imunomodulação: possibilidades terapêuticas e marcadores de prognóstico
• Beneficiário: Ana Paula Lepique
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 08/57889-1 - Instituto de Ciência e Tecnologia para o Estudo das Doenças Associadas ao Papilomavírus
• Beneficiário: Luisa Lina Villa
• Modalidade de apoio: Auxílio à Pesquisa - Temático