Induction of monocyte chemoattractant protein-1 and interleukin-10 by TGFbeta1 in melanoma enhances tumor infiltration and immunosuppression

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-02, Vol.71 (3), p.812-821
• Main Authors: Díaz-Valdés, Nancy, Basagoiti, María, Dotor, Javier, Aranda, Fernando, Monreal, Iñaki, Riezu-Boj, José Ignacio, Borrás-Cuesta, Francisco, Sarobe, Pablo, Feijoó, Esperanza
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Chemokine CCL2 - biosynthesis; Female; Humans; Interleukin-10 - biosynthesis; Interleukin-10 - immunology; MAP Kinase Signaling System; Melanoma - immunology; Melanoma, Experimental - immunology; Mice; Mice, Inbred C57BL; Mice, Nude; Molecular Sequence Data; Monocytes - drug effects; Monocytes - immunology; Proto-Oncogene Proteins c-akt - metabolism; Smad3 Protein - metabolism; Transforming Growth Factor beta1 - pharmacology
• ISSN: 1538-7445
• DOI: 10.1158/0008-5472.Can-10-2698

Melanoma progression is associated with the expression of different growth factors, cytokines, and chemokines. Because TGFβ1 is a pleiotropic cytokine involved not only in physiologic processes but also in cancer development, we analyzed in A375 human melanoma cells, the effect of TGFβ1 on monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10) expression, two known factors responsible for melanoma progression. TGFβ1 increased the expression of MCP-1 and IL-10 in A375 cells, an effect mediated by the cross-talk between Smad, PI3K (phosphoinositide 3-kinase)/AKT, and BRAF-MAPK (mitogen activated protein kinase) signaling pathways. Supernatants from TGFβ1-treated A375 cells enhanced MCP-1-dependent migration of monocytes, which, in turn, expressed high levels of TGF,β1, bFGF, and VEGF mRNA. Moreover, these supernatants also inhibited functional properties of dendritic cells through IL-10-dependent mechanisms. When using in vitro, the TGFβ1-blocking peptide P144, TGFβ1-dependent Smad3 phosphorylation, and expression of MCP-1 and IL-10 were inhibited. In vivo, treatment of A375 tumor-bearing athymic mice with P144 significantly reduced tumor growth, associated with a lower macrophage infiltrate and decreased intratumor MCP-1 and VEGF levels, as well as angiogenesis. Finally, in C57BL/6 mice with B16-OVA melanoma tumors, when administered with immunotherapy, P144 decreased tumor growth and intratumor IL-10 levels, linked to enhanced activation of dendritic cells and natural killer cells, as well as anti-OVA T-cell responses. These results show new effects of TGFβ1 on melanoma cells, which promote tumor progression and immunosuppression, strongly reinforcing the relevance of this cytokine as a molecular target in melanoma.