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<p>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.</p>

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Macrophages foster anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • 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

摘要

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.