Cholesterol Efflux Drives the Generation of Immunosuppressive Macrophages to Promote the Progression of Human Hepatocellular Carcinoma

Abstract

Cholesterol is often enriched in tumor microenvironment (TME); however, its impact on disease progression varies in different tissues and cells. Monocytes/macrophages (Mφ) are major components and regulators of the TME and play pivotal roles in tumor progression and therapeutic responses. We aimed to investigate the profile, effects, and regulatory mechanisms of Mφ cholesterol metabolism in the context of human hepatocellular carcinoma (HCC). Here, we found that patients with high serum levels of cholesterol had shorter survival times and lower response rates to anti-PD-1 treatment. However, the cholesterol content in tumor-infiltrating monocytes/Mφ was significantly lower than that in their counterparts in paired non-tumor tissues. The expression of the cholesterol efflux transporter, ABCA1, was upregulated in tumor monocytes/Mφ, and ABCA1 upregulation positively associated with decreased cellular cholesterol content and increased serum cholesterol levels. Mechanistically, autocrine cytokines from tumor-treated monocytes increased LXRα and ABCA1 expression, which led to the generation of immature and immunosuppressive Mφ. Although exogenous cholesterol alone had little direct effect on Mφ, it did act synergistically with tumor-derived factors to promote ABCA1 expression in Mφ with more immunosuppressive features. Moreover, high numbers of ABCA1+ Mφ in HCC tumors associated with reduced CD8+ T-cell infiltration and predicted poor clinical outcome for patients. Our results revealed that dysregulated cholesterol homeostasis, due to the collaborative effects of tumors and exogenous cholesterol, drives the generation of immunosuppressive Mφ. The selective modulation of cholesterol metabolism in Mφ may represent a novel strategy for cancer treatment.

Cholinergic macrophages promote the resolution of peritoneal inflammation

“…For human MDMs culture, monocytes were isolated from peripheral blood and cultured as previously described ( 45 , 46 ). Briefly, the buffy coats were collected from the blood of healthy individual donors to the Guangzhou Blood Center (Guangzhou, China).…”

Lipid Metabolism as a Potential Target of Liver Cancer

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Dysregulated cholesterol regulatory genes in hepatocellular carcinoma

“…Li et al observed that ABCA1, cholesterol efflux transporter, upregulated in tumor monocytes/macrophages, thereby resulting in the production of immature and immunosuppressive monocytes/macrophages. High numbers of ABCA1 + monocytes/macrophages in HCC decreased CD8 + T cell infiltration, consequently leading to an unfavorable prognosis for HCC [ 58 ]. Cancer stem cells (CSCs) play a vital role in mediating unrestrained cell proliferation and chemoresistance.…”