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

Tumor-associated macrophages (TAMs) dynamically influence anti-tumor immunity. Understanding TAM function and plasticity is therefore critical to design immunotherapies. By combining syngeneic models of colorectal and pancreatic cancer with cell type-specific deletion of Zeb1, a key driver of epithelial-to-mesenchymal transition that is expressed in subsets of TAMs, we discovered that ZEB1 is an intrinsic regulator of TAM-controlled T cell trafficking. ZEB1 supports secretion of a subset of chemokines via the constitutive pathway, including CCL2 and CCL22, by promoting their biosynthesis, vesicular transport and release. This elevates CCL2 and CCL22-driven cytotoxic T cell (CTL) recruitment in vitro and fosters immunosurveillance by CTLs in tumors and metastases as well in an organotypic model for adoptive cell transfer. 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-/ cytokine-depleting strategies.