Data from TGF-β Signaling in Myeloid Cells Is Required for Tumor Metastasis

Abstract

<div>Abstract<p>TGF-β is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-β functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of <i>Tgfbr2</i> specifically in myeloid cells (<i>Tgfbr2</i><sup>MyeKO</sup>) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with <i>Tgfbr2</i><sup>MyeKO</sup> bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-β1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-γ production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the <i>Tgfbr2</i><sup>MyeKO</sup> mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-β receptor II expression. Our studies show that myeloid-specific TGF-β signaling is an essential component of the metastasis-promoting puzzle of TGF-β. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.</p><p><b>Significance:</b> Our study identifies myeloid-specific TGF-β signaling as a critical mediator in tumor metastasis, distinct from the tumor-suppressive effect of TGF-β signaling in epithelial cells, fibroblasts, and T cells. We further provide mechanistic insight into host antitumor immunity and suggest a cell type–specific cancer-targeting strategy. <i>Cancer Discov; 3(8); 936–51. ©2013 AACR</i>.</p><p>See related commentary by Souza-Fonseca-Guimaraes and Smyth, p. 846</p><p>This article is highlighted in the In This Issue feature, p. 826</p></div>