TGFβ signaling in myeloid cells promotes lung and liver metastasis through different mechanisms Stefanescu, Cristina Van Gogh, Merel Roblek, Marko ; https://orcid.org/0000-0001-9588-1389 Heikenwalder, Mathias Borsig, Lubor ddc:610 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. Frontiers 2021 info:eu-repo/semantics/article doc-type:article text http://purl.org/coar/resource_type/c_2df8fbb1 https://research-explorer.ista.ac.at/record/10536 https://research-explorer.ista.ac.at/download/10536/10539 Stefanescu C, Van Gogh M, Roblek M, Heikenwalder M, Borsig L. TGFβ signaling in myeloid cells promotes lung and liver metastasis through different mechanisms. <i>Frontiers in Oncology</i>. 2021;11. doi:<a href="https://doi.org/10.3389/fonc.2021.765151">10.3389/fonc.2021.765151</a> eng info:eu-repo/semantics/altIdentifier/doi/10.3389/fonc.2021.765151 info:eu-repo/semantics/altIdentifier/e-issn/2234-943X info:eu-repo/semantics/altIdentifier/wos/000726603400001 info:eu-repo/semantics/altIdentifier/pmid/34868988 https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess