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

Author:

Menche ConstantinORCID,Schuhwerk HaraldORCID,Armstark Isabell,Gupta Pooja,Fuchs Kathrin,van Roey Ruthger,Mosa Mohammed H,Hartebrodt Anne,Hajjaj Yussuf,Clavel Ezquerra AnaORCID,Selvaraju Manoj K,Geppert Carol I,Bärthel StefanieORCID,Saur DieterORCID,Greten Florian RORCID,Brabletz SimoneORCID,Blumenthal David BORCID,Weigert AndreasORCID,Brabletz ThomasORCID,Farin Henner FORCID,Stemmler Marc PORCID

Abstract

AbstractThe 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.

Funder

Deutsche Forschungsgemeinschaft

Wilhelm Sander-Stiftung

Interdisziplinaeres Zentrum fuer Klinische Forschung, FAU-Erlangen

EC | Horizon 2020 Framework Programme

Bundesministerium für Bildung und Forschung

Publisher

Springer Science and Business Media LLC

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