Gene therapy with interleukin-10 receptor and interleukin-12 induces a protective interferon-gamma-dependent response against B16F10-Nex2 melanoma

Autor(es)

Marchi, L. H. L. ^[1] ; Paschoalin, T. ^[1] ; Travassos, L. R. ^[1] ; Rodrigues, E. G. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Escola Paulista Med, Unidade Oncol Expt, Dept Microbiol Immunol & Parasitol, BR-04023062 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Cancer Gene Therapy; v. 18, n. 2, p. 110-122, FEB 2011.
• Citações Web of Science: 11

Resumo

Antitumor immune responses are associated with proinflammatory cytokines, whereas tumor-developing animals generally have increased the production of immunosuppressive cytokines. Here, we show that splenocytes from C57Bl/6 mice resistant to low doses of B16F10-Nex2 melanoma cells produced twofold or higher interferon-gamma (IFN-gamma)/interleukin-10 (IL-10) ratios, whereas cells from tumor-bearing animals produced predominantly IL-10. IL-10-knockout (IL-10KO) mice were significantly more resistant to B16F10-Nex2 development, producing increased amounts of IL-12 and IFN-gamma. To neutralize IL-10 in vivo, aiming at cancer therapy, recombinant eukaryotic plasmid expressing the soluble extracellular region of the murine IL-10 receptor alpha-chain was constructed (pcDNA3-sIL-10R). Plasmid-treated melanoma-challenged animals showed extended survival time, the protective response was IFN-gamma dependent and enhanced by co-immunization with a plasmid expressing IL-12. Dendritic cells (DCs) from IL-10KO mice, primed with B16F10-Nex2 antigens (TAg), secreted increased amounts of T-helper 1-type cytokines and increased the expression of surface activation markers. Vaccination of C57Bl/6 mice with TAg-activated IL-10KO DCs, as well as with TAg-primed DCs from C57Bl/6 mice transfected with pcDNA3-sIL10R plasmid, significantly increased animal survival. In conclusion, an IFN-gamma-dependent protective response was induced against B16F10-Nex2 cells by neutralization of IL-10 with pcDNA3-sIL10R plasmid. This effect was enhanced by association with IL-12 gene therapy (80% protection), and could be mediated by TAg-primed DCs. Cancer Gene Therapy (2011) 18, 110-122; doi: 10.1038/cgt.2010.58; published online 1 October 2010 (AU)

• Processo FAPESP: 06/50634-2 - Peptídeos e peptidases: atividades biológicas em doenças infecciosas e câncer
• Beneficiário: Luiz Rodolpho Raja Gabaglia Travassos
• Modalidade de apoio: Auxílio à Pesquisa - Temático