Year: 2025
Type: article
Abstract: Tumor-associated macrophages (TAMs) dynamically influence anti-tumor immunity. Understanding TAM function is therefore critical to design immunotherapies. By combining syngeneic models of colorectal and pancreatic cancer with cell type-specific deletion of the epithelial-to-mesenchymal transition driver Zeb1, which is expressed in subsets of TAMs, we discovered that ZEB1 is an intrinsic regulator of TAM-controlled T cell trafficking and anti-tumor immune responses. ZEB1 supports secretion of a subset of chemokines via the constitutive pathway, including CXCL10, CCL2 and CCL22, by regulating their biosynthesis, vesicular transport and release. This elevates cytotoxic T cell (CTL) recruitment in vitro and fosters immunosurveillance by CTLs in tumors and metastases as well in an organotypic model for therapeutic CD8 + T cell addition. Our study identifies ZEB1 in TAMs as a facilitator of anti-tumor immunity, suggests a window of opportunity for cytokine-guided CTL tropism and reinforces the importance of onco-immunological context, particularly in the design of macrophage- and/or cytokine-depleting strategies.
Source: Communications Biology
Authors: Kathrin Fuchs, Elisabetta D’Avanzo, Isabell Armstark, Ruthger van Roey, Ana Clavel Ezquerra, Nino Bindel, Katharina Siebenkäs, Yussuf Hajjaj, Renato Liguori, Fulvia Ferrazzi, Lukas Amon, Johanna Bulang, Julian Hübner, Marcel Edler, Ece Grace, Annemarie Schwab, Marwin Alfredo, Maria Faas, Jochen Ackermann, Elena Percivalle, Claudia Günther, Markus H. Hoffmann, Gerhard Krönke, Christoph Becker, Diana Dudziak, Philipp Arnold, Miriam Woehner, Falk Nimmerjahn, Simone Brabletz, Marc P. Stemmler, Thomas Brabletz, Harald Schuhwerk
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,190
OpenAlex ID: W4411873710