Induction of Monocyte Chemoattractant Protein-1 and Interleukin-10 by TGFβ1 in Melanoma Enhances Tumor Infiltration and Immunosuppression

Nancy Díaz-Valdés,Esperanza Feijoó,Pablo Sarobe,Francisco Borrás-Cuesta,Iñaki Monreal,María Basagoiti,Javier Dotor,Fernando Aranda,José Ignacio Riezu-Boj

doi:10.1158/0008-5472.can-10-2698

Nancy Díaz-Valdés, Esperanza Feijoó + Show 7 more

Open Access

https://doi.org/10.1158/0008-5472.can-10-2698

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Journal: Cancer Research	Publication Date: Feb 1, 2011
Citations: 66	License type: cc-by

Affiliation: University of Navarra

Abstract

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.

Highlights

TGFb1 is a pleiotropic cytokine that plays a relevant role in the progression of cancer due to its effect on cell proliferation, angiogenesis, epithelial-to-mesenchymal transition, and metastasis [1]
To study the effect of TGFb1 on monocyte chemoattractant protein-1 (MCP-1) and IL-10, two known factors associated with melanoma progression, A375 melanoma cells were treated with this cytokine
MCP-1 was constitutively expressed by A375 cells, the addition of TGFb1 significantly increased its expression after 48 hours of culture (Fig. 1A)

Summary

Introduction

TGFb1 is a pleiotropic cytokine that plays a relevant role in the progression of cancer due to its effect on cell proliferation, angiogenesis, epithelial-to-mesenchymal transition, and metastasis [1]. TGFb1 enhances angiogenesis by activating the expression of proangiogenic factors such as interleukin (IL)-8 and VEGF [2]. Tumor cells evade the suppressive effect of TGFb1 through receptor- or Smad-inactivating mutations [7, 8] or by downstream signaling alterations. These modifications avoid the suppressive pathway and induce prometastatic processes [9]. No genetic mutations of TGFb1 classical signaling molecules have been identified in melanoma, a cross-talk between the Smad signaling pathway and other pathways, including Ras/MEK [MAP/ extracellular signal regulated kinase (ERK) kinase]/ERK, and Akt, which are constitutively activated in a large percentage of cutaneous melanomas, has been described [2, 10]

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