Details

Autor(en) / Beteiligte

• Ma, Liqian
• Wang, Lawrence
• Nelson, Adam T.
• Han, Chaeyeon
• He, Sisi
• Henn, Madeline A.
• Menon, Karan
• Chen, Joy J.
• Baek, Amy E.
• Vardanyan, Anna
• Shahoei, Sayyed Hamed
• Park, Sunghee
• Shapiro, David J.
• Nanjappa, Som G.
• Nelson, Erik R.

Titel

27-Hydroxycholesterol acts on myeloid immune cells to induce T cell dysfunction, promoting breast cancer progression

Ist Teil von

• Cancer letters, 2020-11, Vol.493, p.266-283

Ort / Verlag

Ireland: Elsevier B.V

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Breast cancer remains one of the leading causes of cancer mortality in the US. Elevated cholesterol is a major risk factor for breast cancer onset and recurrence, while cholesterol-lowering drugs, such as statins, are associated with a good prognosis. Previous work in murine models showed that cholesterol increases breast cancer metastasis, and the pro-metastatic effects of cholesterol were due to its primary metabolite, 27-hydroxycholesterol (27HC). In our prior work, myeloid cells were found to be required for the pro-metastatic effects of 27HC, but their precise contribution remains unclear. Here we report that 27HC impairs T cell expansion and cytotoxic function through its actions on myeloid cells, including macrophages, in a Liver X receptor (LXR) dependent manner. Many oxysterols and LXR ligands had similar effects on T cell expansion. Moreover, their ability to induce the LXR target gene ABCA1 was associated with their effectiveness in impairing T cell expansion. Induction of T cell apoptosis was likely one mediator of this impairment. Interestingly, the enzyme responsible for the synthesis of 27HC, CYP27A1, is highly expressed in myeloid cells, suggesting that 27HC may have important autocrine or paracrine functions in these cells, a hypothesis supported by our finding that breast cancer metastasis was reduced in mice with a myeloid specific knockout of CYP27A1. Importantly, pharmacologic inhibition of CYP27A1 reduced metastatic growth and improved the efficacy of checkpoint inhibitor, anti-PD-L1. Taken together, our work suggests that targeting the CYP27A1 axis in myeloid cells may present therapeutic benefits and improve the response rate to immune therapies in breast cancer. •The cholesterol metabolite, 27-Hydroxycholesterol (27HC), works on myeloid cells to suppress T cell activity.•27HC-LXR activity mediates myeloid cell-driven immune suppression.•Myeloid cell-driven T cell inhibition likely results from accelerated T cell apoptosis.•Pharmacologic inhibition of 27HC synthesis enhances immune check-point inhibition.•The immune suppression is likely a dominant mechanism by which 27HC promotes breast cancer progression.