Hepatocellular carcinoma (HCC) is a type of cancer that is resistant to immunotherapy due to its high cellular heterogeneity. The heterogeneity of cancer-associated fibroblast (CAF) in HCC tumors was identified through single cell RNA sequencing. CD36(+) CAFs were found to have high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). These cells were derived from hepatic stellate cells. CD36 mediated the expression of MIF through oxidized LDL uptake and activated the lipid peroxidation/p38/CEBPs axis in CD36(+) CAFs, which recruited myeloid-derived suppressor cells (MDSCs) in a MIF- and CD74-dependent manner. Co-implantation of CD36(+) CAFs with HCC cells promoted HCC progression in vivo. Furthermore, a CD36 inhibitor was shown to enhance the effect of anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC.
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.
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