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

Fuchs, K.; Armstark, I.; van Roey, R.; Hajjaj, Y.; D`Avanzo, E.; Liguori, R.; Ferrazzi, F.; Ackermann, J.; Amon, L.; Alfredo, M.; Faas, M.; Huebner, J.; Hoffmann, M. H.; Kroenke, G.; Becker, C.; Dudziak, D.; Nimmerjahn, F.; Brabletz, S.; Stemmler, M. P.; Brabletz, T.; Schuhwerk, H.

doi:10.1101/2024.02.26.582102

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bioRxiv · 10.1101/2024.02.26.582102

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

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Abstract

Tumor-associated macrophages (TAMs) shape the tumor microenvironment (TME) and exert a decisive impact on anti-tumor immunity. Understanding TAM function is therefore critical to understand anti-tumor immune responses and to design immunotherapies. Here, we describe the transcription factor ZEB1, a well-known driver of epithelial-to-mesenchymal transition, as an intrinsic regulator of TAM function in adaptive anti-tumor immunity. By combining cell type-specific deletion of Zeb1 with syngeneic models of colorectal and pancreatic cancer, we discovered an unexpected function of ZEB1 in the TAM-mediated control of T cell trafficking. ZEB1 supports secretion of a subset of chemokines including CCL2 and CCL22 by promoting their transcription and translation as well as by safeguarding protein processing. ZEB1 thereby elevates cytotoxic T cell (CTL) recruitment in vitro and in vivo and fosters immunosurveillance during tumor as well as lung metastatic outgrowth. Our study spotlights ZEB1 as a crucial facilitator of adaptive anti-tumor immunity and uncovers a potential therapeutic window of opportunity for cytokine-guided enhancement of CTL infiltration into tumors and metastases.

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Fuchs, K., Armstark, I., van Roey, R., Hajjaj, Y., D`Avanzo, E., Liguori, R., Ferrazzi, F., Ackermann, J., Amon, L., Alfredo, M., Faas, M., Huebner, J., Hoffmann, M. H., Kroenke, G., Becker, C., Dudziak, D., Nimmerjahn, F., Brabletz, S., Stemmler, M. P., Brabletz, T., Schuhwerk, H.. 2024-03-01. Macrophages foster adaptive anti-tumor immunity by ZEB1-dependent cytotoxic T cell chemoattraction. https://doi.org/10.1101/2024.02.26.582102

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