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

TGF-beta is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-beta functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeK0)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeK0) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-beta 1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-gamma production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeK0) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-beta receptor II expression. Our studies show that myeloid-specific TGF-beta signaling is an essential component of the metastasis-promoting puzzle of TGF-beta. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells.