ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer

• Published in: EMBO reports 2024-08, Vol.25 (8), p.3406-3431
• Main Authors: Menche, Constantin, Schuhwerk, Harald, Armstark, Isabell, Gupta, Pooja, Fuchs, Kathrin, van Roey, Ruthger, Mosa, Mohammed H, Hartebrodt, Anne, Hajjaj, Yussuf, Clavel Ezquerra, Ana, Selvaraju, Manoj K, Geppert, Carol I, Bärthel, Stefanie, Saur, Dieter, Greten, Florian R, Brabletz, Simone, Blumenthal, David B, Weigert, Andreas, Brabletz, Thomas, Farin, Henner F, Stemmler, Marc P
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Cell Line, Tumor; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; EMBO03; EMBO19; EMBO37; Epithelial-Mesenchymal Transition - genetics; Fibroblasts - metabolism; Gene Expression Regulation, Neoplastic; Humans; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy - methods; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Life Sciences; Mice; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00186-7

The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers are reduced. Single-cell transcriptomics, histological characterization, and in vitro modeling reveal a crucial role of ZEB1 in CAF polarization, promoting myofibroblastic features by restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases NFκB-mediated cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1 -deficient CAF repertoire sensitizes to immune checkpoint inhibition, offering a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis. Synopsis Fibroblast-specific Zeb1 knock-out in colorectal cancer models leads to a shift in myCAF and iCAF populations, promoting immune infiltration. This increases colitis-associated tumorigenesis, reduces progression and metastasis and renders tumors susceptible to immune checkpoint blockade. Zeb1 loss in cancer-associated fibroblasts (CAFs) accelerates inflammation-driven colorectal tumorigenesis. In sporadic tumors CAF-specific Zeb1-loss results in decreased progression and metastasis. Impaired myofibroblast and increased inflammation result in increased immune cell infiltration and checkpoint activation. Zeb1 deficiency in CAFs sensitizes colorectal cancers to immune checkpoint inhibition. Fibroblast-specific Zeb1 knock-out in colorectal cancer models leads to a shift in myCAF and iCAF populations, promoting immune infiltration. This increases colitis-associated tumorigenesis, reduces progression and metastasis and renders tumors susceptible to immune checkpoint blockade.