Abstract

Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36+ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36+CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36+ CAFs, which recruited CD33+myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36+ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.

Details

Title
CD36+ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor
Author
Zhu, Gui-Qi 1 ; Tang, Zheng 1 ; Huang, Run 1 ; Qu, Wei-Feng 1 ; Fang, Yuan 1 ; Yang, Rui 1 ; Tao, Chen-Yang 1 ; Gao, Jun 1 ; Wu, Xiao-Ling 1 ; Sun, Hai-Xiang 1 ; Zhou, Yu-Fu 2 ; Song, Shu-Shu 3 ; Ding, Zhen-Bin 1   VIAFID ORCID Logo  ; Dai, Zhi 4 ; Zhou, Jian 1   VIAFID ORCID Logo  ; Ye, Dan 5 ; Wu, Duo-Jiao 6 ; Liu, Wei-Ren 1 ; Fan, Jia 1   VIAFID ORCID Logo  ; Shi, Ying-Hong 1 

1  Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443); Chinese Academy of Medical Sciences, Research Unit of Liver cancer Recurrence and Metastasis, Beijing, China (GRID:grid.506261.6) (ISNI:0000 0001 0706 7839) 
2  Shanghai University of Traditional Chinese Medicine, Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai, China (GRID:grid.412540.6) (ISNI:0000 0001 2372 7462) 
3  Fudan University, Department of Biochemistry and Molecular, School of Basic Medical Sciences, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
4  Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
5  Shanghai Medical College of Fudan University, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Key Laboratory of Metabolism and Molecular Medicine (Ministry of Education), and Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai, China (GRID:grid.11841.3d) (ISNI:0000 0004 0619 8943) 
6  Fudan University, Institute of Clinical Science, Zhongshan Hospital, Shanghai, China (GRID:grid.8547.e) (ISNI:0000 0001 0125 2443) 
Pages
25
Publication year
2023
Publication date
2023
Publisher
Springer Nature B.V.
e-ISSN
20565968
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41421-023-00529-z
ProQuest document ID
2783532105
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.