The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer

Jia-Jun Li, Jin-Hong Wang, Tian Tian, Jia Liu, Yong-Qiang Zheng, Hai-Yu Mo, Hui Sheng, Yan-Xing Chen, Qi-Nian Wu, Yi Han, Kun Liao, Yi-Qian Pan, Zhao-Lei Zeng, Ze-Xian Liu, Wei Yang, Rui-Hua Xu () and Huai-Qiang Ju ()
Additional contact information
Jia-Jun Li: Sun Yat-sen University Cancer Center
Jin-Hong Wang: Sun Yat-sen University Cancer Center
Tian Tian: Jinan University, Guangzhou
Jia Liu: Sun Yat-sen University Cancer Center
Yong-Qiang Zheng: Sun Yat-sen University Cancer Center
Hai-Yu Mo: Sun Yat-sen University Cancer Center
Hui Sheng: Sun Yat-sen University Cancer Center
Yan-Xing Chen: Sun Yat-sen University Cancer Center
Qi-Nian Wu: Sun Yat-sen University Cancer Center
Yi Han: Guangdong Academy of Medical Sciences, Guangzhou
Kun Liao: Sun Yat-sen University Cancer Center
Yi-Qian Pan: Sun Yat-sen University Cancer Center
Zhao-Lei Zeng: Sun Yat-sen University Cancer Center
Ze-Xian Liu: Sun Yat-sen University Cancer Center
Wei Yang: Guangdong Academy of Medical Sciences, Guangzhou
Rui-Hua Xu: Sun Yat-sen University Cancer Center
Huai-Qiang Ju: Sun Yat-sen University Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1β in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.

Date: 2023
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DOI: 10.1038/s41467-023-42332-0

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