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

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.

Identification of a Lipid Homeostasis Related Genes Signature in Predicting the Prognosis, Immunity, and Chemotherapeutic Effect for Patients With Gastric Cancer

“…Fibroblasts in the TME were also known as carcinoma-associated broblasts (CAFs), which were critically associated with tumorgenesis and tumor progression by boosting angiogenesis, cancer cell proliferation, and invasion. Gui-Qi Zhu reported that CD36 + CAFs in the hepatocellular carcinoma showed high level lipid metabolism and secreted macrophage migration inhibitory factor via the lipid peroxidation/p38/CEBPs axis, leading to an immunosuppressive TME and tumor stemness (Zhu et al 2023). Additionally, after reprogramming of lipid metabolism, lipids metabolites secreted by CAFs were proved to promote CRC migration in a CD36 dependent manner (Gong et al 2020).…”

Lipid metabolism marker CD36 is associated with 18FDG-PET/CT false negative lymph nodes in head and neck squamous cell carcinoma

“…Et.al observed that metastasis-associated macrophages (MAM) upregulate CD36, which fuel macrophage-tumor crosstalk and reshape the TME ( 34 ). In TME of hepatocellular carcinoma (HCC), a subcluster of cancer-associated fibroblast (CAF) expressed CD36 exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF), which interacted with HCC and myeloid-derived suppressor cells to provide immunosuppressive microenvironment ( 35 ). However, despite of quantities of molecular biology studies on CD36, it has not been applied with 18 FDG-PET/CT for distinguishing false negatives yet.…”

Novel insights into HBV‐hepatocellular carcinoma at single‐cell sequencing

“…Partial single‐cell studies have highlighted the relevance of the CAFs‐dominated immune barrier in HBV‐HCC immunotherapy. CD36 + CAFs (Table 3) transformed from hepatic stellate cells have been reported to exhibit high levels of lipid metabolism and macrophage migration inhibitory factor (MIF) expression, which were associated with immune evasion 86 . Also, it was stated that CAFs could interact with SPP1 + macrophages to form a tumor immune barrier (TIB) to restrain the infiltration of immune cells into the tumor foci 87 .…”