27-Hydroxycholesterol promotes breast cancer progression through the modulation of myeloid cells

Ma, Liqian

Permalink

https://hdl.handle.net/2142/113941 Copy

Description

Title

27-Hydroxycholesterol promotes breast cancer progression through the modulation of myeloid cells

Author(s)

Ma, Liqian

Issue Date

2021-08-11

Director of Research (if dissertation) or Advisor (if thesis)

Nelson, Erik R

Doctoral Committee Chair(s)

Nelson, Erik R

Committee Member(s)

• Raetzman, Lori
• Sinha, Saurabh
• Johnson, Rodney

Department of Study

Molecular & Integrative Physi

Discipline

Molecular & Integrative Physi

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• 27-hydroxycholesterol
• breast cancer

Abstract

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). Myeloid cells were found to be required for the pro-metastatic effects of 27HC, but their precise contribution remains unclear. We show 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, cytochrome P450 family 27 subfamily A member 1 (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. Previous reports also showed protective effect of synthetic activation of LXR in cancer models. To address this paradox, RNA sequencing of macrophages treated with 27HC and synthetic ligands of the LXR and estrogen receptor (ER) revealed the selective LXR modulatory potential of 27HC, similar to desmosterol, compared to the synthetic agonists/antagonists. Inside breast tumor microenvironment, single-cell RNAseq showed that 27HC also exerted distinct effects on even closely related myeloid-derive imunne populations, compared to GW3965. 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. It is also possible to devise synthetic selective modulators of LXR to augment the beneficial effects of its activation, while avoiding 27HC-driven immunosuppression. Our work ultimately provided a foundation for the future development of cancer therapeutics targeting cholesterol-LXR axis.

Graduation Semester

2021-12

Type of Resource

Thesis

Permalink

http://hdl.handle.net/2142/113941

Copyright and License Information

Copyright 2021 Liqian Ma

Owning Collections