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TGFβ overexpression is commonly detected in cancer patients and correlates with poor prognosis and metastasis. Cancer progression is often associated with an enhanced recruitment of myeloid-derived cells to the tumor microenvironment. Here we show that functional TGFβ-signaling in myeloid cells is required for metastasis to the lungs and the liver. Myeloid-specific deletion of Tgfbr2 resulted in reduced spontaneous lung metastasis, which was associated with a reduction of proinflammatory cytokines in the metastatic microenvironment. Notably, CD8 +  T cell depletion in myeloid-specific  Tgfbr2 -deficient mice rescued lung metastasis. Myeloid-specific  Tgfbr2 -deficiency resulted in reduced liver metastasis with an almost complete absence of myeloid cells within metastatic foci. On contrary, an accumulation of Tgfβ-responsive myeloid cells was associated with an increased recruitment of monocytes and granulocytes and higher proinflammatory cytokine levels in control mice. Monocytic cells isolated from metastatic livers of  Tgfbr2 -deficient mice showed increased polarization towards the M1 phenotype, Tnfα and Il-1β expression, reduced levels of M2 markers and reduced production of chemokines responsible for myeloid-cell recruitment. No significant differences in Tgfβ levels were observed at metastatic sites of any model. These data demonstrate that Tgfβ signaling in monocytic myeloid cells suppresses CD8 +  T cell activity during lung metastasis, while these cells actively contribute to tumor growth during liver metastasis. Thus, myeloid cells modulate metastasis through different mechanisms in a tissue-specific manner.

TGFβ Signaling in Myeloid Cells Promotes Lung and Liver Metastasis Through Different Mechanisms