CD36+ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor

Gui-Qi Zhu; Zheng Tang; Run Huang; Wei-Feng Qu; Yuan Fang; Rui Yang; Chen-Yang Tao; Jun Gao; Xiao-Ling Wu; Hai-Xiang Sun; Yu-Fu Zhou; Shu-Shu Song; Zhen-Bin Ding; Zhi Dai; Jian Zhou; Dan Ye; Duo-Jiao Wu; Wei-Ren Liu; Jia Fan; Ying-Hong Shi

doi:10.1038/s41421-023-00529-z

CD36⁺ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor

Cell Discov. 2023 Mar 6;9(1):25. doi: 10.1038/s41421-023-00529-z.

Authors

Gui-Qi Zhu^#^{1

2}, Zheng Tang^#^{1

2}, Run Huang^#^{1

2}, Wei-Feng Qu^#^{1

2}, Yuan Fang^{1

2}, Rui Yang^{1

2}, Chen-Yang Tao^{1

2}, Jun Gao^{1

2}, Xiao-Ling Wu^{1

2}, Hai-Xiang Sun^{1

2}, Yu-Fu Zhou³, Shu-Shu Song⁴, Zhen-Bin Ding^{1

2}, Zhi Dai¹, Jian Zhou^{1

2}, Dan Ye⁵, Duo-Jiao Wu⁶, Wei-Ren Liu^{7

8}, Jia Fan^{9

10}, Ying-Hong Shi^{11

12}

Affiliations

¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.
² Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China.
³ Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁴ Department of Biochemistry and Molecular, School of Basic Medical Sciences, Fudan University, Shanghai, China.
⁵ 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 Medical College of Fudan University, Shanghai, China.
⁶ Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China.
⁷ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China. liu.weiren@zs-hospital.sh.cn.
⁸ Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China. liu.weiren@zs-hospital.sh.cn.
⁹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China. fan.jia@zs-hospital.sh.cn.
¹⁰ Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China. fan.jia@zs-hospital.sh.cn.
¹¹ Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China. shi.yinghong@zs-hospital.sh.cn.
¹² Research Unit of Liver cancer Recurrence and Metastasis, Chinese Academy of Medical Sciences, Beijing, China. shi.yinghong@zs-hospital.sh.cn.

^# Contributed equally.

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.

Abstract

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