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oai:www.ideals.illinois.edu:2142/113941 2023-07-11 col_2142_5131 col_2142_16508 com_2142_5130 com_2142_16507 com_2142_14793 com_2142_8903

Nelson, Erik R Nelson, Erik R Raetzman, Lori Sinha, Saurabh Johnson, Rodney 2022-04-29T21:41:40Z 2024-04-29T21:47:53Z 2021-12 Submission published under a 24 month embargo labeled 'U of I Access', the embargo will last until 2023-12-01 The student, Liqian Ma, accepted the attached license on 2021-08-04 at 16:20. The student, Liqian Ma, submitted this Dissertation for approval on 2021-08-04 at 16:29. This Dissertation was approved for publication on 2021-08-11 at 08:46. DSpace SAF Submission Ingestion Package generated from Vireo submission #17099 on 2022-04-06 at 17:16:11 Made available in DSpace on 2022-04-29T21:41:40Z (GMT). No. of bitstreams: 2 MA-DISSERTATION-2021.pdf: 9265330 bytes, checksum: 9c06953f8fd076556994d92c9cddf8d4 (MD5) LICENSE.txt: 4206 bytes, checksum: b80fc1cf8fb01e59ce356ee348464ccf (MD5) Previous issue date: 2021-08-11 Embargo set by: Seth Robbins for item 123302 Lift date: 2024-04-29T21:41:44Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 123302 Lift date: 2024-04-29T21:42:24Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 123302 Lift date: 2024-04-29T21:43:01Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 123302 Lift date: 2024-04-29T21:44:44Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 123302 Lift date: 2024-04-29T21:46:25Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Embargo set by: Seth Robbins for item 123302 Lift date: 2024-04-29T21:47:53Z Reason: Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system Author requested U of Illinois access only (OA after 2yrs) in Vireo ETD system U of I Only application/pdf en text 27-Hydroxycholesterol promotes breast cancer progression through the modulation of myeloid cells Ma, Liqian 2021-08-11 27-hydroxycholesterol breast cancer 2022-04-29T21:41:40Z 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. text eng http://hdl.handle.net/2142/113941 Copyright 2021 Liqian Ma Molecular & Integrative Physi Molecular & Integrative Physi University of Illinois at Urbana-Champaign Dissertation Ph.D.