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SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion
Breast cancer is the most commonly diagnosed cancer and among the leading causes of death among women in the United States. Our previous work has found that a metabolite of cholesterol, 27-hydroxycholesterol (27HC) promotes breast cancer metastasis in preclinical models. 27HC is a ligand of both the...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552196/ http://dx.doi.org/10.1210/js.2019-SAT-340 |
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author | Ma, Liqian Baek, Amy Nelson, Erik |
author_facet | Ma, Liqian Baek, Amy Nelson, Erik |
author_sort | Ma, Liqian |
collection | PubMed |
description | Breast cancer is the most commonly diagnosed cancer and among the leading causes of death among women in the United States. Our previous work has found that a metabolite of cholesterol, 27-hydroxycholesterol (27HC) promotes breast cancer metastasis in preclinical models. 27HC is a ligand of both the estrogen receptor (ER) and liver X receptor (LXR). Intriguingly, the pro-metastatic effects of 27HC require the presence of myeloid-immune cells. This cell type has been implicated in suppressing acquired immunity, allowing cancer cells to escape immune surveillance. Therefore, we hypothesized that 27HC suppresses the immune system to promote metastasis. To elucidate the immunomodulatory capacity of 27HC, we co-cultured vehicle- or 27HC-treated bone marrow-derived macrophages (BMDMs) with T cells. In support of our hypothesis, we found that 27HC-treated BMDMs inhibited T cell expansion in a dose-dependent manner. Additionally, co-cultured BMDMs treated with 27HC resulted in decreased granzyme B in CD8+ cytotoxic T cells, potentially reducing their capacity to kill cancer cells. The immunosuppressive effect of 27HC-treated BMDMs persisted even without a direct contact between BMDMs and T cells, suggesting that the T cell inhibition is unlikely due to 27HC’s modulation of macrophages’ cell surface markers, in particular MHCII and CD80/86, which are commonly used for BMDM-T cell communication. In order to determine the mechanisms by which 27HC-treated BMDMs suppress T cell proliferation, we first evaluated the relative contributions of two receptors known to bind 27HC: the ERs and LXRs. To this end, BMDMs were exposed to pharmacologic antagonists of, or siRNA against the ERs or LXRs. These BMDMs were subsequently co-cultured with activated T cells to study their impact on T cell proliferation. Interestingly, 27HC’s immunosuppressive capacity required LXR in BMDMs, but not ER, as both siRNA knockdown and pharmacological inhibition of LXR significantly rescued the BMDM-inhibited T cell expansion. A subsequent cytokine array indicated that 27HC treatment could induce the secretion of anti-inflammatory cytokines, potential mediators of the observed decrease in T cell expansion. Therefore, our results suggest that 27HC affects the microenvironment of breast cancer by altering the activity of antigen-presenting cells through the modulation of LXR. This in turn reduces the expansion of T cell function, ultimately resulting in immune escape and tumor progression. Our ongoing work is aimed at elucidating the 27HC-induced LXR signaling pathway in BMDMs and further identifying the downstream targets of 27HC involved in mediating this immunosuppressive phenotype. Our work is of considerable importance given the prevalence of hypercholesterolemia as well as metastatic breast cancer. This work was supported by the grants from the NCI and DOD-BCRP to ERN (R00CA172357, BC171214). |
format | Online Article Text |
id | pubmed-6552196 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-65521962019-06-13 SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion Ma, Liqian Baek, Amy Nelson, Erik J Endocr Soc Tumor Biology Breast cancer is the most commonly diagnosed cancer and among the leading causes of death among women in the United States. Our previous work has found that a metabolite of cholesterol, 27-hydroxycholesterol (27HC) promotes breast cancer metastasis in preclinical models. 27HC is a ligand of both the estrogen receptor (ER) and liver X receptor (LXR). Intriguingly, the pro-metastatic effects of 27HC require the presence of myeloid-immune cells. This cell type has been implicated in suppressing acquired immunity, allowing cancer cells to escape immune surveillance. Therefore, we hypothesized that 27HC suppresses the immune system to promote metastasis. To elucidate the immunomodulatory capacity of 27HC, we co-cultured vehicle- or 27HC-treated bone marrow-derived macrophages (BMDMs) with T cells. In support of our hypothesis, we found that 27HC-treated BMDMs inhibited T cell expansion in a dose-dependent manner. Additionally, co-cultured BMDMs treated with 27HC resulted in decreased granzyme B in CD8+ cytotoxic T cells, potentially reducing their capacity to kill cancer cells. The immunosuppressive effect of 27HC-treated BMDMs persisted even without a direct contact between BMDMs and T cells, suggesting that the T cell inhibition is unlikely due to 27HC’s modulation of macrophages’ cell surface markers, in particular MHCII and CD80/86, which are commonly used for BMDM-T cell communication. In order to determine the mechanisms by which 27HC-treated BMDMs suppress T cell proliferation, we first evaluated the relative contributions of two receptors known to bind 27HC: the ERs and LXRs. To this end, BMDMs were exposed to pharmacologic antagonists of, or siRNA against the ERs or LXRs. These BMDMs were subsequently co-cultured with activated T cells to study their impact on T cell proliferation. Interestingly, 27HC’s immunosuppressive capacity required LXR in BMDMs, but not ER, as both siRNA knockdown and pharmacological inhibition of LXR significantly rescued the BMDM-inhibited T cell expansion. A subsequent cytokine array indicated that 27HC treatment could induce the secretion of anti-inflammatory cytokines, potential mediators of the observed decrease in T cell expansion. Therefore, our results suggest that 27HC affects the microenvironment of breast cancer by altering the activity of antigen-presenting cells through the modulation of LXR. This in turn reduces the expansion of T cell function, ultimately resulting in immune escape and tumor progression. Our ongoing work is aimed at elucidating the 27HC-induced LXR signaling pathway in BMDMs and further identifying the downstream targets of 27HC involved in mediating this immunosuppressive phenotype. Our work is of considerable importance given the prevalence of hypercholesterolemia as well as metastatic breast cancer. This work was supported by the grants from the NCI and DOD-BCRP to ERN (R00CA172357, BC171214). Endocrine Society 2019-04-30 /pmc/articles/PMC6552196/ http://dx.doi.org/10.1210/js.2019-SAT-340 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Tumor Biology Ma, Liqian Baek, Amy Nelson, Erik SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion |
title | SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion |
title_full | SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion |
title_fullStr | SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion |
title_full_unstemmed | SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion |
title_short | SAT-340 27-Hydroxycholesterol Acts on Myeloid Cells to Inhibit T Cell Expansion |
title_sort | sat-340 27-hydroxycholesterol acts on myeloid cells to inhibit t cell expansion |
topic | Tumor Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6552196/ http://dx.doi.org/10.1210/js.2019-SAT-340 |
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