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Cited by 98Cancer, Lipids, and MetabolismImmune cells in cancerCholesterol and Lipid Metabolism

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

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Ma, Liqian, Wang, Lawrence, Nelson, Adam T., Han, Chaeyeon, He, Sisi, Henn, Madeline A., Menon, Karan, Chen, Joy J. +7 more·2020·Cancer Letters
DOI 10.1016/j.canlet.2020.08.020PMC PMC7572761
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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). 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.

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  • 27-hydroxycholesterol works through liver x receptors in myeloid immune cells to suppress T cell proliferation and function, stimulate secretion of pro-tumor extracellular vesicles, and promote tumor and metastatic growth.

    “An oxysterol metabolite of cholesterol, 27-hydroxycholesterol, was found to work through the liver x receptors in myeloid immune cells to robustly suppress T cell proliferation and function, and stimulate the secretion of pro-tumor extracellular vesicles, ultimately promoting the growth of tumors and metastatic lesions (17, 20–23).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [22]

    The Results report that 27-hydroxycholesterol acts through LXRs in myeloid cells to impair T-cell expansion, and that it increases metastatic burden in mouse models. But the Results section on macrophage secretion found no difference in the effects of extracellular vesicles from treated and untreated macrophages; it concludes that vesicles are unlikely to mediate the observed T-cell suppression. The paper therefore does not support the attributed claim that 27-hydroxycholesterol stimulates secretion of pro-tumor extracellular vesicles. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Treatment of BMDMs with cholesterol is known to impair their support of T cell expansion, in part through conversion to the immune-suppressive 27-hydroxycholesterol and activation of the LXRs.

    “Treatment of BMDMs with cholesterol is known to impair their support of T cell expansion, in part through conversion to the immune-suppressive 27-hydroxycholesterol and activation of the LXRs (22, 23).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [22]

    The Results sections on 27HC-treated macrophages and LXR report that 27HC-treated BMDMs suppress T-cell expansion and that LXR inhibition attenuates this effect (page unavailable). The paper also reports greater T-cell expansion with CYP27A1-deficient BMDMs, consistent with a role for macrophage-produced 27HC. It does not show that treating BMDMs with cholesterol impairs their support of T-cell expansion or establish that conversion of the added cholesterol causes that effect. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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  1. [1]Siegel RL, Miller KD, Jemal A, Cancer statistics, 2020, CA Cancer J Clin, 70 (2020) 7– 30. 31912902
  2. [2]Sharma R, Breast cancer incidence, mortality and mortality-to-incidence ratio (MIR) are associated with human development, 1990–2016: evidence from Global Burden of Disease Study 2016, Breast Cancer, 26 (2019) 428– 445. 30604398
  3. [3]DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, Jemal A, Siegel RL, Breast cancer statistics, 2019, CA Cancer J Clin, 69 (2019) 438– 451. 31577379
  4. [4]Munoz D, Near AM, van Ravesteyn NT, Lee SJ, Schechter CB, Alagoz O, Berry DA, Burnside ES, Chang Y, Chisholm G, de Koning HJ, Ali Ergun M, Heijnsdijk EA, Huang H, Stout NK, Sprague BL, Trentham-Dietz A, Mandelblatt JS, Plevritis SK, Effects of screening and systemic adjuvant therapy on ER-specific US breast cancer mortality, J Natl Cancer Inst, 106 (2014). PMC4271026 25255803
  5. [5]Polk A, Svane IM, Andersson M, Nielsen D, Checkpoint inhibitors in breast cancer - Current status, Cancer Treat Rev, 63 (2018) 122– 134. 29287242
  6. [6]Swoboda A, Nanda R, Immune Checkpoint Blockade for Breast Cancer, Cancer Treat Res, 173 (2018) 155– 165. 29349763 PMC6061922
  7. [7]Fares CM, Van Allen EM, Drake CG, Allison JP, Hu-Lieskovan S, Mechanisms of Resistance to Immune Checkpoint Blockade: Why Does Checkpoint Inhibitor Immunotherapy Not Work for All Patients?, Am Soc Clin Oncol Educ Book, 39 (2019) 147– 164. 31099674
  8. [8]Vonderheide RH, Domchek SM, Clark AS, Immunotherapy for Breast Cancer: What Are We Missing?, Clin Cancer Res, 23 (2017) 2640– 2646. 28572258 PMC5480967
  9. [9]Basu A, Ramamoorthi G, Jia Y, Faughn J, Wiener D, Awshah S, Kodumudi K, Czerniecki BJ, Immunotherapy in breast cancer: Current status and future directions, Adv Cancer Res, 143 (2019) 295– 349. 31202361
  10. [10]Jahchan NS, Mujal AM, Pollack JL, Binnewies M, Sriram V, Reyno L, Krummel MF, Tuning the Tumor Myeloid Microenvironment to Fight Cancer, Front Immunol, 10 (2019) 1611. 31402908 PMC6673698
  11. [11]Racioppi L, Nelson ER, Huang W, Mukherjee D, Lawrence SA, Lento W, Masci AM, Jiao Y, Park S, York B, Liu Y, Baek AE, Drewry DH, Zuercher WJ, Bertani FR, Businaro L, Geradts J, Hall A, Means AR, Chao N, Chang CY, McDonnell DP, CaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer, Nat Commun, 10 (2019) 2450. 31164648 PMC6547743
  12. [13]Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, Gil V, Boysen G, Losa M, Mosole S, Pasquini E, D’Antuono R, Masetti M, Zagato E, Chiorino G, Ostano P, Rinaldi A, Gnetti L, Graupera M, Martins Figueiredo Fonseca AR, Pereira Mestre R, Waugh D, Barry S, De Bono J, Alimonti A, Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer, Cell Rep, 28 (2019) 2156– 2168. e2155. 31433989 PMC6715643
  13. [14]Yan D, Kowal J, Akkari L, Schuhmacher AJ, Huse JT, West BL, Joyce JA, Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas, Oncogene, 36 (2017) 6049– 6058. 28759044 PMC5666319
  14. [15]Baek AE, Nelson ER, The Contribution of Cholesterol and Its Metabolites to the Pathophysiology of Breast Cancer, Horm Cancer, 7 (2016) 219– 228. 27020054 PMC4930376
  15. [16]Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, Sotgia F, Lisanti MP, Frank PG, Role of cholesterol in the development and progression of breast cancer, Am J Pathol, 178 (2011) 402– 412. 21224077 PMC3069824
  16. [17]Bahl M, Ennis M, Tannock IF, Hux JE, Pritchard KI, Koo J, Goodwin PJ, Serum lipids and outcome of early-stage breast cancer: results of a prospective cohort study, Breast Cancer Res Treat, 94 (2005) 135– 144. 16261412
  17. [18]Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, Sorensen HT, Lash TL, Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study, J Natl Cancer Inst, 103 (2011) 1461– 1468. 21813413 PMC3186780
  18. [19]Brewer TM, Masuda H, Liu DD, Shen Y, Liu P, Iwamoto T, Kai K, Barnett CM, Woodward WA, Reuben JM, Yang P, Hortobagyi GN, Ueno NT, Statin use in primary inflammatory breast cancer: a cohort study, Br J Cancer, 109 (2013) 318– 324. 23820253 PMC3721387
  19. [20]Borgquist S, Broberg P, Tojjar J, Olsson H, Statin use and breast cancer survival - a Swedish nationwide study, BMC Cancer, 19 (2019) 54. 30634941 PMC6330431
  20. [21]Beckwitt CH, Brufsky A, Oltvai ZN, Wells A, Statin drugs to reduce breast cancer recurrence and mortality, Breast Cancer Res, 20 (2018) 144. 30458856 PMC6247616
  21. [22]Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J, McDonnell DP, 27-Hydroxycholesterol links hypercholesterolemia and breast cancer pathophysiology, Science, 342 (2013) 1094– 1098. 24288332 PMC3899689
  22. [23]Baek AE, Yu YA, He S, Wardell SE, Chang CY, Kwon S, Pillai RV, McDowell HB, Thompson JW, Dubois LG, Sullivan PM, Kemper JK, Gunn MD, McDonnell DP, Nelson ER, The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells, Nat Commun, 8 (2017) 864. 29021522 PMC5636879
  23. [24]He S, Ma L, Baek AE, Vardanyan A, Vembar V, Chen JJ, Nelson AT, Burdette JE, Nelson ER, Host CYP27A1 expression is essential for ovarian cancer progression, Endocr Relat Cancer, (2019). PMC6824983 31048561
  24. [25]Morita Y, Zhang R, Leslie M, Adhikari S, Hasan N, Chervoneva I, Rui H, Tanaka T, Pathologic evaluation of tumor-associated macrophage density and vessel inflammation in invasive breast carcinomas, Oncol Lett, 14 (2017) 2111– 2118. 28789438 PMC5530034
  25. [26]Soncin I, Sheng J, Chen Q, Foo S, Duan K, Lum J, Poidinger M, Zolezzi F, Karjalainen K, Ruedl C, The tumour microenvironment creates a niche for the self-renewal of tumour-promoting macrophages in colon adenoma, Nat Commun, 9 (2018) 582. 29422500 PMC5805689
  26. [27]Ai L, Mu S, Wang Y, Wang H, Cai L, Li W, Hu Y, Prognostic role of myeloid-derived suppressor cells in cancers: a systematic review and meta-analysis, BMC Cancer, 18 (2018) 1220. 30518340 PMC6280417
  27. [28]Toor SM, Syed Khaja AS, El Salhat H, Faour I, Kanbar J, Quadri AA, Albashir M, Elkord E, Myeloid cells in circulation and tumor microenvironment of breast cancer patients, Cancer Immunol Immunother, 66 (2017) 753– 764. 28283696 PMC5445142
  28. [29]Awad RM, De Vlaeminck Y, Maebe J, Goyvaerts C, Breckpot K, Turn Back the TIMe: Targeting Tumor Infiltrating Myeloid Cells to Revert Cancer Progression, Front Immunol, 9 (2018) 1977. 30233579 PMC6127274
  29. [30]Quatromoni JG, Eruslanov E, Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer, Am J Transl Res, 4 (2012) 376– 389. 23145206 PMC3493031
  30. [32]Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, Pisarev V, Sherman S, Sporn MB, Gabrilovich D, Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice, J Clin Invest, 121 (2011) 4015– 4029. 21911941 PMC3195459
  31. [33]Dujaily EA, Baena J, Das M, Sereno M, Smith C, Kamata T, Officer L, Pritchard C, Le Quesne J, Reduced pro-tumourigenic tumour-associated macrophages with statin use in premalignant human lung adenocarcinoma, JNCI Cancer Spectrum, (2019). PMC7068793 32190817
  32. [35]Dumitru CD, Ceci JD, Tsatsanis C, Kontoyiannis D, Stamatakis K, Lin JH, Patriotis C, Jenkins NA, Copeland NG, Kollias G, Tsichlis PN, TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway, Cell, 103 (2000) 1071– 1083. 11163183
  33. [36]Xiao L, Ornatowska M, Zhao G, Cao H, Yu R, Deng J, Li Y, Zhao Q, Sadikot RT, Christman JW, Lipopolysaccharide-induced expression of microsomal prostaglandin E synthase-1 mediates late-phase PGE2 production in bone marrow derived macrophages, PLoS One, 7 (2012) e50244. 23226252 PMC3511480
  34. [37]Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC, CD14 controls the LPS-induced endocytosis of Toll-like receptor 4, Cell, 147 (2011) 868– 880. 22078883 PMC3217211
  35. [38]Nelson ER, DuSell CD, Wang X, Howe MK, Evans G, Michalek RD, Umetani M, Rathmell JC, Khosla S, Gesty-Palmer D, McDonnell DP, The oxysterol, 27-hydroxycholesterol, links cholesterol metabolism to bone homeostasis through its actions on the estrogen and liver × receptors, Endocrinology, 152 (2011) 4691– 4705. 21933863 PMC3230052
  36. [39]Nelson ER, Li S, Kennedy M, Payne S, Kilibarda K, Groth J, Bowie M, Parilla-Castellar E, de Ridder G, Marcom PK, Lyes M, Peterson BL, Cook M, Pizzo SV, McDonnell DP, Bachelder RE, Chemotherapy enriches for an invasive triple-negative breast tumor cell subpopulation expressing a precursor form of N-cadherin on the cell surface, Oncotarget, 7 (2016) 84030– 84042. 27768598 PMC5356642
  37. [40]Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E, Cerami E, Sander C, Schultz N, Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal, Sci Signal, 6 (2013) pl1. 23550210 PMC4160307
  38. [41]Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N, The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data, Cancer Discov, 2 (2012) 401– 404. 22588877 PMC3956037
  39. [42]Benjamini Y, Hochberg Y, Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing, Journal of the Royal Statistical Society. Series B (Methodological), 57 (1995) 289– 300.
  40. [43]Ma L, Nelson ER, Oxysterols and nuclear receptors, Molecular and cellular endocrinology, 484 (2019) 42– 51. 30660701
  41. [44]Ma L, Nelson ER, Oxysterols and nuclear receptors, Molecular and cellular endocrinology, (2019). 30660701
  42. [45]Shi Y, Xu X, Tan Y, Mao S, Fang S, Gu W, A liver-X-receptor ligand, T0901317, attenuates IgE production and airway remodeling in chronic asthma model of mice, PloS One, 9 (2014) e92668. 24681543 PMC3969355
  43. [46]Thomas DG, Doran AC, Fotakis P, Westerterp M, Antonson P, Jiang H, Jiang X-C, Gustafsson J-Å, Tabas I, Tall AR, LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux, Cell reports, 25 (2018) 3774– 3785. e3774. 30590048 PMC6446575
  44. [47]Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P, LXR signaling couples sterol metabolism to proliferation in the acquired immune response, Cell, 134 (2008) 97– 111. 18614014 PMC2626438
  45. [48]Sato T, Terai M, Tamura Y, Alexeev V, Mastrangelo MJ, Selvan SR, Interleukin 10 in the tumor microenvironment: a target for anticancer immunotherapy, Immunol Res, 51 (2011) 170– 182. 22139852
  46. [49]Pello OM, De Pizzol M, Mirolo M, Soucek L, Zammataro L, Amabile A, Doni A, Nebuloni M, Swigart LB, Evan GI, Mantovani A, Locati M, Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology, Blood, 119 (2012) 411– 421. 22067385
  47. [50]Barnden MJ, Allison J, Heath WR, Carbone FR, Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements, 76 (1998) 34– 40. 9553774
  48. [52]Qi C, Cai Y, Gunn L, Ding C, Li B, Kloecker G, Qian K, Vasilakos J, Saijo S, Iwakura Y, Yannelli JR, Yan J, Differential pathways regulating innate and adaptive antitumor immune responses by particulate and soluble yeast-derived beta-glucans, Blood, 117 (2011) 6825– 6836. 21531981 PMC3128477
  49. [53]Zhou F, Rouse BT, Huang L, Prolonged survival of thymoma-bearing mice after vaccination with a soluble protein antigen entrapped in liposomes: a model study, Cancer Res, 52 (1992) 6287– 6291. 1384958
  50. [54]Nelson ER, The significance of cholesterol and its metabolite, 27-hydroxycholesterol in breast cancer, Molecular and cellular endocrinology, (2017). PMC5854519 28919300
  51. [55]Revilla G, Pons MP, Baila-Rueda L, Garcia-Leon A, Santos D, Cenarro A, Magalhaes M, Blanco RM, Moral A, Ignacio Perez J, Sabe G, Gonzalez C, Fuste V, Lerma E, Faria MDS, de Leiva A, Corcoy R, Carles Escola-Gil J, Mato E, Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness, Sci Rep, 9 (2019) 10260. 31311983 PMC6635382
  52. [56]Zou W, Immunosuppressive networks in the tumour environment and their therapeutic relevance, Nat Rev Cancer, 5 (2005) 263– 274. 15776005
  53. [57]Mondanelli G, Iacono A, Allegrucci M, Puccetti P, Grohmann U, Immunoregulatory Interplay Between Arginine and Tryptophan Metabolism in Health and Disease, Front Immunol, 10 (2019) 1565. 31354721 PMC6629926
  54. [58]Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, Meng X, Li L, Wang J, Xu C, Yan C, Wang L, Chang CC, Chang TY, Zhang T, Zhou P, Song BL, Liu W, Sun SC, Liu X, Li BL, Xu C, Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism, Nature, 531 (2016) 651– 655. 26982734 PMC4851431
  55. [59]Reiss AB, Vernice NA, Siegart NM, De Leon J, Kasselman LJ, Exosomes in Cholesterol Metabolism and Atherosclerosis, Cardiovasc Hematol Disord Drug Targets, 17 (2017) 185– 194. 29299993
  56. [60]Castano C, Kalko S, Novials A, Parrizas M, Obesity-associated exosomal miRNAs modulate glucose and lipid metabolism in mice, Proc Natl Acad Sci U S A, 115 (2018) 12158– 12163. 30429322 PMC6275521
  57. [61]Wang T, Nasser MI, Shen J, Qu S, He Q, Zhao M, Functions of Exosomes in the Triangular Relationship between the Tumor, Inflammation, and Immunity in the Tumor Microenvironment, J Immunol Res, 2019 (2019) 4197829. 31467934 PMC6701352
  58. [62]Ortiz A, Gui J, Zahedi F, Yu P, Cho C, Bhattacharya S, Carbone CJ, Yu Q, Katlinski KV, Katlinskaya YV, Handa S, Haas V, Volk SW, Brice AK, Wals K, Matheson NJ, Antrobus R, Ludwig S, Whiteside TL, Sander C, Tarhini AA, Kirkwood JM, Lehner PJ, Guo W, Rui H, Minn AJ, Koumenis C, Diehl JA, Fuchs SY, An Interferon-Driven Oxysterol-Based Defense against Tumor-Derived Extracellular Vesicles, Cancer Cell, 35 (2019) 33– 45 e36. 30645975 PMC6336114
  59. [63]Ben-Sasson SZ, Hogg A, Hu-Li J, Wingfield P, Chen X, Crank M, Caucheteux S, Ratner-Hurevich M, Berzofsky JA, Nir-Paz R, Paul WE, IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells, J Exp Med, 210 (2013) 491– 502. 23460726 PMC3600912
  60. [64]Di Paolo NC, Shayakhmetov DM, Interleukin 1alpha and the inflammatory process, Nat Immunol, 17 (2016) 906– 913. 27434011 PMC5152572
  61. [65]Santarlasci V, Cosmi L, Maggi L, Liotta F, Annunziato F, IL-1 and T Helper Immune Responses, Front Immunol, 4 (2013) 182. 23874332 PMC3711056
  62. [66]Lichtman AH, Chin J, Schmidt JA, Abbas AK, Role of interleukin 1 in the activation of T lymphocytes, Proc Natl Acad Sci U S A, 85 (1988) 9699– 9703. 3264404 PMC282842
  63. [67]Nelson ER, Wardell SE, Jasper JS, Park S, Suchindran S, Howe MK, Carver NJ, Pillai RV, Sullivan PM, Sondhi V, Umetani M, Geradts J, McDonnell DP, 27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology, Science (New York, N.Y.), 342 (2013) 1094– 1098. PMC3899689 24288332
  64. [68]Dalenc F, Poirot M, Silvente-Poirot S, Dendrogenin A: A Mammalian Metabolite of Cholesterol with Tumor Suppressor and Neurostimulating Properties, Curr Med Chem, 22 (2015) 3533– 3549. 26179999
  65. [69]de Medina P, Paillasse MR, Segala G, Voisin M, Mhamdi L, Dalenc F, Lacroix-Triki M, Filleron T, Pont F, Saati TA, Morisseau C, Hammock BD, Silvente-Poirot S, Poirot M, Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties, Nat Commun, 4 (2013) 1840. 23673625 PMC3674249
  66. [70]Svoronos N, Perales-Puchalt A, Allegrezza MJ, Rutkowski MR, Payne KK, Tesone AJ, Nguyen JM, Curiel TJ, Cadungog MG, Singhal S, Eruslanov EB, Zhang P, Tchou J, Zhang R, Conejo-Garcia JR, Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells, Cancer Discov, 7 (2017) 72– 85. 27694385 PMC5222699
  67. [71]Andruska N, Mao C, Cherian M, Zhang C, Shapiro DJ, Evaluation of a luciferase-based reporter assay as a screen for inhibitors of estrogen-ERalpha-induced proliferation of breast cancer cells, J Biomol Screen, 17 (2012) 921– 932. 22498909 PMC4132978
  68. [72]Murphy AJ, Guyre PM, Wira CR, Pioli PA, Estradiol regulates expression of estrogen receptor ERalpha46 in human macrophages, PLoS One, 4 (2009) e5539. 19440537 PMC2678254
  69. [73]Bolego C, Cignarella A, Staels B, Chinetti-Gbaguidi G, Macrophage function and polarization in cardiovascular disease: a role of estrogen signaling?, Arterioscler Thromb Vasc Biol, 33 (2013) 1127– 1134. 23640494
  70. [75]Wardell SE, Marks JR, McDonnell DP, The turnover of estrogen receptor alpha by the selective estrogen receptor degrader (SERD) fulvestrant is a saturable process that is not required for antagonist efficacy, Biochem Pharmacol, 82 (2011) 122– 130. 21501600 PMC3109090
  71. [76]Patel R, Magomedova L, Tsai R, Angers S, Orellana A, Cummins CL, Separating the Anti-Inflammatory and Diabetogenic Effects of Glucocorticoids Through LXRβ Antagonism, Endocrinology, 158 (2017) 1034– 1047. 28324010
  72. [78]Fan J, Zhao RQ, Parro C, Zhao W, Chou HY, Robert J, Deeb TZ, Raynoschek C, Barichievy S, Engkvist O, Maresca M, Hicks R, Meuller J, Moss SJ, Brandon NJ, Wood MW, Kulic I, Wellington CL, Small molecule inducers of ABCA1 and apoE that act through indirect activation of the LXR pathway, J Lipid Res, 59 (2018) 830– 842. 29563219 PMC5928439
  73. [79]Bang BR, Li M, Tsai KN, Aoyagi H, Lee SA, Machida K, Aizaki H, Jung JU, Ou JJ, Saito T, Regulation of Hepatitis C Virus Infection by Cellular Retinoic Acid Binding Proteins through the Modulation of Lipid Droplet Abundance, J Virol, 93 (2019). PMC6450116 30728260
  74. [80]Zuercher WJ, Buckholz RG, Campobasso N, Collins JL, Galardi CM, Gampe RT, Hyatt SM, Merrihew SL, Moore JT, Oplinger JA, Reid PR, Spearing PK, Stanley TB, Stewart EL, Willson TM, Discovery of tertiary sulfonamides as potent liver × receptor antagonists, Journal of medicinal chemistry, 53 (2010) 3412– 3416. 20345102
  75. [81]Griffett K, Burris TP, Promiscuous activity of the LXR antagonist GSK2033 in a mouse model of fatty liver disease, Biochem Biophys Res Commun, 479 (2016) 424– 428. 27680310 PMC5087326
  76. [83]Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S, Woo G, Nguyen AV, Figueiredo CC, Foubert P, Schmid MC, Pink M, Winkler DG, Rausch M, Palombella VJ, Kutok J, McGovern K, Frazer KA, Wu X, Karin M, Sasik R, Cohen EE, Varner JA, PI3Kgamma is a molecular switch that controls immune suppression, Nature, 539 (2016) 437– 442. 27642729 PMC5479689
  77. [84]Gerberick GF, Cruse LW, Miller CM, Sikorski EE, Ridder GM, Selective modulation of T cell memory markers CD62L and CD44 on murine draining lymph node cells following allergen and irritant treatment, Toxicol Appl Pharmacol, 146 (1997) 1– 10. 9299591
  78. [85]Munn DH, Pressey J, Beall AC, Hudes R, Alderson MR, Selective activation-induced apoptosis of peripheral T cells imposed by macrophages. A potential mechanism of antigen-specific peripheral lymphocyte deletion, J Immunol, 156 (1996) 523– 532. 8543802
  79. [87]Daigneault M, De Silva TI, Bewley MA, Preston JA, Marriott HM, Mitchell AM, Mitchell TJ, Read RC, Whyte MK, Dockrell DH, Monocytes regulate the mechanism of T-cell death by inducing Fas-mediated apoptosis during bacterial infection, PLoS Pathog, 8 (2012) e1002814. 22829769 PMC3400568
  80. [88]Vassena L, Giuliani E, Koppensteiner H, Bolduan S, Schindler M, Doria M, HIV-1 Nef and Vpu Interfere with L-Selectin (CD62L) Cell Surface Expression To Inhibit Adhesion and Signaling in Infected CD4+ T Lymphocytes, J Virol, 89 (2015) 5687– 5700. 25822027 PMC4442509
  81. [89]Sachet M, Liang YY, Oehler R, The immune response to secondary necrotic cells, Apoptosis, 22 (2017) 1189– 1204. 28861714 PMC5630647
  82. [90]Crowley LC, Marfell BJ, Scott AP, Waterhouse NJ, Quantitation of Apoptosis and Necrosis by Annexin V Binding, Propidium Iodide Uptake, and Flow Cytometry, Cold Spring Harb Protoc, 2016 (2016). 27803250
  83. [91]Bedner E, Smolewski P, Amstad P, Darzynkiewicz Z, Activation of caspases measured in situ by binding of fluorochrome-labeled inhibitors of caspases (FLICA): correlation with DNA fragmentation, Exp Cell Res, 259 (2000) 308– 313. 10942603
  84. [92]Darzynkiewicz Z, Pozarowski P, Lee BW, Johnson GL, Fluorochrome-labeled inhibitors of caspases: convenient in vitro and in vivo markers of apoptotic cells for cytometric analysis, Methods Mol Biol, 682 (2011) 103– 114. 21057924 PMC3059744
  85. [94]Zhu X, Lang J, Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer, Oncotarget, 8 (2017) 97671– 97682. 29228642 PMC5722594
  86. [95]Nelson ER, Chang CY, McDonnell DP, Cholesterol and breast cancer pathophysiology, Trends Endocrinol Metab, 25 (2014) 649– 655. 25458418 PMC4268141
  87. [96]Torres CG, Ramirez ME, Cruz P, Epunan MJ, Valladares LE, Sierralta WD, 27-hydroxycholesterol induces the transition of MCF7 cells into a mesenchymal phenotype, Oncol Rep, 26 (2011) 389– 397. 21567091
  88. [97]Yu YR, O’Koren EG, Hotten DF, Kan MJ, Kopin D, Nelson ER, Que L, Gunn MD, A Protocol for the Comprehensive Flow Cytometric Analysis of Immune Cells in Normal and Inflamed Murine Non-Lymphoid Tissues, PLoS One, 11 (2016) e0150606. 26938654 PMC4777539
  89. [98]Kim IS, Gao Y, Welte T, Wang H, Liu J, Janghorban M, Sheng K, Niu Y, Goldstein A, Zhao N, Bado I, Lo HC, Toneff MJ, Nguyen T, Bu W, Jiang W, Arnold J, Gu F, He J, Jebakumar D, Walker K, Li Y, Mo Q, Westbrook TF, Zong C, Rao A, Sreekumar A, Rosen JM, Zhang XH, Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms, Nature cell biology, 21 (2019) 1113– 1126. 31451770 PMC6726554
  90. [99]Marengo B, Bellora F, Ricciarelli R, De Ciucis C, Furfaro A, Leardi R, Colla R, Pacini D, Traverso N, Moretta A, Pronzato MA, Bottino C, Domenicotti C, Oxysterol mixture and, in particular, 27-hydroxycholesterol drive M2 polarization of human macrophages, BioFactors (Oxford, England), 42 (2016) 80– 92. 26669587
  91. [100]Gong B, Kiyotani K, Sakata S, Nagano S, Kumehara S, Baba S, Besse B, Yanagitani N, Friboulet L, Nishio M, Takeuchi K, Kawamoto H, Fujita N, Katayama R, Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer, J Exp Med, 216 (2019) 982– 1000. 30872362 PMC6446862
  92. [101]Mahoney KM, Shukla SA, Patsoukis N, Chaudhri A, Browne EP, Arazi A, Eisenhaure TM, Pendergraft WF 3rd, Hua P, Pham HC, Bu X, Zhu B, Hacohen N, Fritsch EF, Boussiotis VA, Wu CJ, Freeman GJ, A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression, Cancer immunology, immunotherapy: CII, 68 (2019) 421– 432. 30564891 PMC6426808
  93. [102]He XH, Xu LH, Liu Y, Identification of a novel splice variant of human PD-L1 mRNA encoding an isoform-lacking Igv-like domain, Acta Pharmacol Sin, 26 (2005) 462– 468. 15780196
  94. [103]Wu Q, Ishikawa T, Sirianni R, Tang H, McDonald JG, Yuhanna IS, Thompson B, Girard L, Mineo C, Brekken RA, Umetani M, Euhus DM, Xie Y, Shaul PW, 27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast cancer growth, Cell reports, 5 (2013) 637– 645. 24210818 PMC3950897
  95. [104]Shi SZ, Lee EJ, Lin YJ, Chen L, Zheng HY, He XQ, Peng JY, Noonepalle SK, Shull AY, Pei FC, Deng LB, Tian XL, Deng KY, Shi H, Xin HB, Recruitment of monocytes and epigenetic silencing of intratumoral CYP7B1 primarily contribute to the accumulation of 27-hydroxycholesterol in breast cancer, American journal of cancer research, 9 (2019) 2194– 2208. 31720082 PMC6834472
  96. [105]Mutemberezi V, Buisseret B, Masquelier J, Guillemot-Legris O, Alhouayek M, Muccioli GG, Oxysterol levels and metabolism in the course of neuroinflammation: insights from in vitro and in vivo models, J Neuroinflammation, 15 (2018) 74. 29523207 PMC5845224
  97. [106]Ahsan F, Maertzdorf J, Guhlich-Bornhof U, Kaufmann SHE, Moura-Alves P, IL-36/LXR axis modulates cholesterol metabolism and immune defense to Mycobacterium tuberculosis, Sci Rep, 8 (2018) 1520. 29367626 PMC5784124
  98. [107]Shahoei SH, Nelson ER, Nuclear receptors, cholesterol homeostasis and the immune system, The Journal of steroid biochemistry and molecular biology, 191 (2019) 105364. 31002862 PMC6589364
  99. [108]Umetani M, Ghosh P, Ishikawa T, Umetani J, Ahmed M, Mineo C, Shaul PW, The cholesterol metabolite 27-hydroxycholesterol promotes atherosclerosis via proinflammatory processes mediated by estrogen receptor alpha, Cell Metab, 20 (2014) 172– 182. 24954418 PMC4098728
  100. [109]Yin K, You Y, Swier V, Tang L, Radwan MM, Pandya AN, Agrawal DK, Vitamin D Protects Against Atherosclerosis via Regulation of Cholesterol Efflux and Macrophage Polarization in Hypercholesterolemic Swine, Arteriosclerosis, thrombosis, and vascular biology, 35 (2015) 2432– 2442. PMC4618721 26381871
  101. [110]Oguro H, McDonald JG, Zhao Z, Umetani M, Shaul PW, Morrison SJ, 27-Hydroxycholesterol induces hematopoietic stem cell mobilization and extramedullary hematopoiesis during pregnancy, J Clin Invest, 127 (2017) 3392– 3401. 28783041 PMC5669562
  102. [111]Ma L, Nelson ER, Oxysterols and nuclear receptors, Mol Cell Endocrinol, 484 (2019) 42– 51. 30660701
  103. [112]Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O’Connell RM, Cheng G, Saez E, Miller JF, Tontonoz P, LXR-dependent gene expression is important for macrophage survival and the innate immune response, Cell, 119 (2004) 299– 309. 15479645
  104. [113]Endo-Umeda K, Nakashima H, Umeda N, Seki S, Makishima M, Dysregulation of Kupffer Cells/Macrophages and Natural Killer T Cells in Steatohepatitis in LXRalpha Knockout Male Mice, Endocrinology, 159 (2018) 1419– 1432. 29409022
  105. [114]Gargiulo S, Gamba P, Testa G, Rossin D, Biasi F, Poli G, Leonarduzzi G, Relation between TLR4/NF-kappaB signaling pathway activation by 27-hydroxycholesterol and 4-hydroxynonenal, and atherosclerotic plaque instability, Aging Cell, 14 (2015) 569– 581. 25757594 PMC4531071
  106. [115]Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O’Connell RM, Cheng G, Saez E, Miller JF, Tontonoz P, LXR-Dependent Gene Expression Is Important for Macrophage Survival and the Innate Immune Response, Cell, 119 (2004) 299– 309. 15479645
  107. [117]Yu SX, Chen W, Hu XZ, Feng SY, Li KY, Qi S, Lei QQ, Hu GQ, Li N, Zhou FH, Ma CY, Du CT, Yang YJ, Liver × receptors agonists suppress NLRP3 inflammasome activation, Cytokine, 91 (2017) 30– 37. 27987394
  108. [118]Wei Q, Mu K, Li T, Zhang Y, Yang Z, Jia X, Zhao W, Huai W, Guo P, Han L, Deregulation of the NLRP3 inflammasome in hepatic parenchymal cells during liver cancer progression, Lab Invest, 94 (2014) 52– 62. 24166187
  109. [119]Moossavi M, Parsamanesh N, Bahrami A, Atkin SL, Sahebkar A, Role of the NLRP3 inflammasome in cancer, Mol Cancer, 17 (2018) 158. 30447690 PMC6240225
  110. [120]Kimbung S, Chang CY, Bendahl PO, Dubois L, Thompson JW, McDonnell DP, Borgquist S, Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer, Endocr Relat Cancer, 24 (2017) 339– 349. 28442559
  111. [121]Sun L, Clavijo PE, Robbins Y, Patel P, Friedman J, Greene S, Das R, Silvin C, Van Waes C, Horn LA, Schlom J, Palena C, Maeda D, Zebala J, Allen CT, Inhibiting myeloid-derived suppressor cell trafficking enhances T cell immunotherapy, JCI Insight, 4 (2019). PMC6483637 30944253
  112. [122]De Henau O, Rausch M, Winkler D, Campesato LF, Liu C, Cymerman DH, Budhu S, Ghosh A, Pink M, Tchaicha J, Douglas M, Tibbitts T, Sharma S, Proctor J, Kosmider N, White K, Stern H, Soglia J, Adams J, Palombella VJ, McGovern K, Kutok JL, Wolchok JD, Merghoub T, Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells, Nature, 539 (2016) 443– 447. 27828943 PMC5634331
  113. [123]Flores-Toro JA, Luo D, Gopinath A, Sarkisian MR, Campbell JJ, Charo IF, Singh R, Schall TJ, Datta M, Jain RK, Mitchell DA, Harrison JK, CCR2 inhibition reduces tumor myeloid cells and unmasks a checkpoint inhibitor effect to slow progression of resistant murine gliomas, Proc Natl Acad Sci U S A, 117 (2020) 1129– 1138. 31879345 PMC6969504
  114. [124]Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ, An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha, Nature, 383 (1996) 728– 731. 8878485
  115. [125]Kim WK, Meliton V, Tetradis S, Weinmaster G, Hahn TJ, Carlson M, Nelson SF, Parhami F, Osteogenic oxysterol, 20(S)-hydroxycholesterol, induces notch target gene expression in bone marrow stromal cells, J Bone Miner Res, 25 (2010) 782– 795. 19839776 PMC3153332
  116. [126]Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ, Structural requirements of ligands for the oxysterol liver × receptors LXRalpha and LXRbeta, Proc Natl Acad Sci U S A, 96 (1999) 266– 271. 9874807 PMC15128
  117. [127]Wang CW, Huang CC, Chou PH, Chang YP, Wei S, Guengerich FP, Chou YC, Wang SF, Lai PS, Soucek P, Ueng YF, 7-ketocholesterol and 27-hydroxycholesterol decreased doxorubicin sensitivity in breast cancer cells: estrogenic activity and mTOR pathway, Oncotarget, 8 (2017) 66033– 66050. 29029490 PMC5630390
  118. [128]Lappano R, Recchia AG, De Francesco EM, Angelone T, Cerra MC, Picard D, Maggiolini M, The cholesterol metabolite 25-hydroxycholesterol activates estrogen receptor alpha-mediated signaling in cancer cells and in cardiomyocytes, PLoS One, 6 (2011) e16631. 21304949 PMC3031608
  119. [129]Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, Javitt NB, Korach KS, Shaul PW, Mangelsdorf DJ, 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen, Nat Med, 13 (2007) 1185– 1192. 17873880
  120. [130]Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG, 27-hydroxycholesterol is an endogenous ligand for liver × receptor in cholesterol-loaded cells, J Biol Chem, 276 (2001) 38378– 38387. 11504730
  121. [131]Crestani M, De Fabiani E, Caruso D, Mitro N, Gilardi F, Vigil Chacon AB, Patelli R, Godio C, Galli G, LXR (liver × receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport, Biochem Soc Trans, 32 (2004) 92– 96. 14748721
  122. [132]Poirot M, Silvente-Poirot S, The tumor-suppressor cholesterol metabolite, dendrogenin A, is a new class of LXR modulator activating lethal autophagy in cancers, Biochem Pharmacol, 153 (2018) 75– 81. 29409832
  123. [133]Silvente-Poirot S, Segala G, Poirot MC, Poirot M, Ligand-dependent transcriptional induction of lethal autophagy: A new perspective for cancer treatment, Autophagy, 14 (2018) 555– 557. 29368971 PMC5915042
  124. [134]Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, Reichart D, Fox JN, Shaked I, Heudobler D, Raetz CR, Wang EW, Kelly SL, Sullards MC, Murphy RC, Merrill AH Jr., Brown HA, Dennis EA, Li AC, Ley K, Tsimikas S, Fahy E, Subramaniam S, Quehenberger O, Russell DW, Glass CK, Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses, Cell, 151 (2012) 138– 152. 23021221 PMC3464914
  125. [135]Muse ED, Yu S, Edillor CR, Tao J, Spann NJ, Troutman TD, Seidman JS, Henke A, Roland JT, Ozeki KA, Thompson BM, McDonald JG, Bahadorani J, Tsimikas S, Grossman TR, Tremblay MS, Glass CK, Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages, Proc Natl Acad Sci U S A, 115 (2018) E4680– e4689. 29632203 PMC5960280

Cited by

Sorted by citations

Authors
Ma, L., Wang, L., Nelson, A. T., Han, C., He, S., Henn, M. A., Menon, K., Chen, J. J., Baek, A. E., Vardanyan, A., Shahoei, S. H., Park, S., Shapiro, D. J., Nanjappa, S. G., & Nelson, E. R.
Affiliations
University of Illinois Urbana-Champaign (US)
Corresponding author
Nelson, Erik R.
ORCID
Venue
Cancer Letters
Publisher
Elsevier BV
Published
2020-11
Volume
493
Pages
266-283
ISSN
0304-3835 (ISSN-L)
DOI
10.1016/j.canlet.2020.08.020
PMC
PMC7572761
OpenAlex
W3082411788
Cited by
98
References
10
Citations by year
2026: 14 · 2025: 20 · 2024: 15 · 2023: 22 · 2022: 14 · 2021: 12 · 2020: 1
FWCI
4.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Letters (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • California Breast Cancer Research Program (R01DK071909, BC171214)
  • U.S. Department of Defense
  • American Institute for Cancer Research (579732)
  • National Institutes of Health (R01DK071909, R01CA234025)
  • METAvivor
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
27-hydroxycholesterol, breast cancer metastasis, myeloid cells, macrophages, T cell dysfunction, T cell expansion, cytotoxic T lymphocytes, liver X receptor, ABCA1, CYP27A1, oxysterols, T cell apoptosis, immunotherapy
MeSH terms
Liver X Receptors, Animals, Breast Neoplasms, Female, Humans, Hydroxycholesterols, Neoplasm Transplantation, T-Lymphocytes, Myeloid Cells, Cell Line, Tumor, Mice, Cholestanetriol 26-Monooxygenase, Gene Knockout Techniques, ATP Binding Cassette Transporter 1

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