Cell Discovery (Mar 2023)

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
https://doi.org/10.1038/s41421-023-00529-z
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 22

Abstract

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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.