2. Academic Validation
  3. The liver microenvironment orchestrates FGL1-mediated immune escape and progression of metastatic colorectal cancer

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

  • Nat Commun. 2023 Oct 23;14(1):6690. doi: 10.1038/s41467-023-42332-0.
Jia-Jun Li # 1,  Jin-Hong Wang # 1,  Tian Tian # 2,  Jia Liu # 1,  Yong-Qiang Zheng 1,  Hai-Yu Mo 1,  Hui Sheng 1,  Yan-Xing Chen 1,  Qi-Nian Wu 1,  Yi Han 3,  Kun Liao 1,  Yi-Qian Pan 1,  Zhao-Lei Zeng 1,  Ze-Xian Liu 1,  Wei Yang 3,  Rui-Hua Xu 4 5,  Huai-Qiang Ju 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
  • 2 Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, 510632, Guangdong, China.
  • 3 Research Department of Medical Sciences, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, Guangdong, China.
  • 4 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. xurh@sysucc.org.cn.
  • 5 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, Guangdong, China. xurh@sysucc.org.cn.
  • 6 State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China. juhq@sysucc.org.cn.
  • 7 Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, 510060, Guangdong, China. juhq@sysucc.org.cn.
  • # Contributed equally.
PMID: 37872170 DOI: 10.1038/s41467-023-42332-0
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.

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