CD36 Cancer-associated Fibroblasts Provide Immunosuppressive Microenvironment for Hepatocellular Carcinoma Via Secretion of Macrophage Migration Inhibitory Factor

Overview

Journal Cell Discov

Date 2023 Mar 6

PMID 36878933

Authors

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

Affiliations

Soon will be listed here.

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 CD36CAFs 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 CD33myeloid-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.

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