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

• Published in: Cell discovery Vol. 9; no. 1; pp. 25 - 22
• Main Authors: Zhu, Gui-Qi, Tang, Zheng, Huang, Run, Qu, Wei-Feng, Fang, Yuan, Yang, Rui, Tao, Chen-Yang, Gao, Jun, Wu, Xiao-Ling, Sun, Hai-Xiang, Zhou, Yu-Fu, Song, Shu-Shu, Ding, Zhen-Bin, Dai, Zhi, Zhou, Jian, Ye, Dan, Wu, Duo-Jiao, Liu, Wei-Ren, Fan, Jia, Shi, Ying-Hong
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 06.03.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1059/2325; 631/67/2329; 631/67/327; Antitumor activity; Biomedical and Life Sciences; CD36 antigen; Cell Biology; Cell Culture; Cell Cycle Analysis; Cell Physiology; Cells; Fibroblasts; Genes; Hepatitis B; Hepatocellular carcinoma; Immune system; Immunotherapy; Leukocyte migration; Life Sciences; Lipid metabolism; Lipid peroxidation; Lipids; Liver cancer; Low density lipoprotein; Lymphocytes T; Macrophage migration inhibitory factor; Malignancy; Medical prognosis; PD-1 protein; Stellate cells; Stem Cells; Suppressor cells; Tumor cells; Tumor microenvironment; Tumors
• ISSN: 2056-5968; 2056-5968
• DOI: 10.1038/s41421-023-00529-z

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.