Medicine in focus
Cholesterol metabolism: At the cross road between cancer cells and immune environment

https://doi.org/10.1016/j.biocel.2020.105876Get rights and content

Highlights

  • Cholesterol and its metabolites synthesized by cancer cells influence initiation, progression and drug resistance.

  • Some of these metabolites effluxed by cancer cells modulate the functions of immune infiltrating cells in tumor environment.

  • Pharmacological inhibitors targeting cholesterol metabolism could be repurposed as immune adjuvant agents.

Abstract

Mevalonate pathway is a highly conserved pathway that produces isoprenoids and cholesterol, and it is often increased in cancer cells. Cholesterol, upstream metabolites including isoprenoids and cholesterol derivatives such as oxysterols modulate cell proliferation, motility, stemness and drug resistance. Moreover, when produced by cancer cells or immune infiltrating cells, they modulate the activity of immune populations of the tumor microenvironment. In this review, we will focus on the recent findings demonstrating that cholesterol derivatives may regulate tumor immune recognition or immune escape, playing a critical role in the immune surveillance. Since the mevalonate pathway is druggable, a deeper knowledge of the metabolic cross talks existing between the mevalonate pathway of cancer cells and immune cells may help to identify novel agents targeting cholesterol metabolism, able to boost the anti-tumor activity of the immune populations.

Section snippets

Cholesterol metabolism in cancer

Cholesterol is synthesized from acetyl Coenzyme A (AcCoA) in the so called “mevalonate (MVA) pathway”. Most of the enzymes of the MVA pathway are upregulated in tumors (Yang et al., 2020). This finding explains why tumor tissues have higher levels of cholesterol than non-transformed tissues. The pacemaker enzyme 3-β-3-hydroxymethylglutaryl Coenzyme A reductase (HMGCR) is a sterol sensitive enzyme and is transcriptionally induced by the sterol regulatory element binding proteins (SREBPs) (Lee et

Cholesterol metabolism regulates the tumor-immune system interaction

If cancer cells have usually a high MVA pathway activity, immune cells display a variable situation, depending on their state. Upon activation, the canonical anti-tumor populations – cytotoxic CD8+T lymphocytes, M1 polarized tumor associated macrophages (TAMs) and mature dendritic cells (DCs) – upregulate the Ras/PI3K/mTOR axis that increases SREBP transcriptional activity and MVA pathway. By contrast, quiescent or tumor tolerant immune cells – such as memory T lymphocytes, M2 polarized TAMs,

Therapeutic implications of targeting cholesterol metabolism and future perspectives

Despite the high MVA pathway activity in cancer cells, all the regulatory mechanisms are still preserved and sensitive to pharmacological inhibitors. Modulating cholesterol metabolism may have a deep impact on the immune recognition of cancer cells. Statins and aminobisphosphonates, inhibitors of HMGCR and FPP synthase, respectively, have been already used in various cancer types. The HMG synthase inhibitor dipyridamole, the squalene epoxidase inhibitor terfinabine, as well as inhibitors of

Funding

This work was supported by the Italian Association of Cancer Research (AIRC; IG21408 to CR). The funding agency has no role in preparing the manuscript.

Declaration of Competing Interest

The authors report no declarations of interest.

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