NR0B2 re-educates myeloid immune cells to reduce regulatory T cell expansion and progression of breast and other solid tumors
Open accessAbstract
Although survival from breast cancer has dramatically increased, many will develop recurrent, metastatic disease. Unfortunately, survival for this stage of disease remains very low. Activating the immune system has incredible promise since it has the potential to be curative. However, immune checkpoint blockade (ICB) which works through T cells has been largely disappointing for metastatic breast cancer. One reason for this is a suppressive myeloid immune compartment that is unaffected by ICB. Cholesterol metabolism and proteins involved in cholesterol homeostasis play important regulatory roles in myeloid cells. Here, we demonstrate that NR0B2, a nuclear receptor involved in negative feedback of cholesterol metabolism, works in several myeloid cell types to impair subsequent expansion of regulatory T cells (Tregs); Tregs being a subset known to be highly immune suppressive and associated with poor therapeutic response. Within myeloid cells, NR0B2 serves to decrease many aspects of the inflammasome, ultimately resulting in decreased IL1β; IL1β driving Treg expansion. Importantly, mice lacking NR0B2 exhibit accelerated tumor growth. Thus, NR0B2 represents an important node in myeloid cells dictating ensuing Treg expansion and tumor growth, thereby representing a novel therapeutic target to re-educate these cells, having impact across different solid tumor types. Indeed, a paper co-published in this issue demonstrates the therapeutic utility of targeting NR0B2.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NR0B2 suppresses several aspects of the inflammasome in myeloid cells, resulting in decreased expansion of regulatory T cells.
“The negative regulator of cholesterol catabolism, NR0B2, was found to suppress several aspects of the inflammasome in myeloid cells, resulting in decreased expansion of regulatory T cells (Tregs) (24, 25).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [25]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
A novel heterodimeric cysteine protease is required for interleukin-1βprocessing in monocytes
Thornberry, N., Bull, H., Calaycay, J., Chapman, K., Howard, A., Kostura, M., Miller, D. K., Molineaux, S., Weidner, J., Auniņš, J., et al. (1992) · Nature · doi:10.1038/356768a0 · Cited by 2,725 · cited 1× · see citing works
“Caspase 1 is a cysteine protease, with one of its major substrates being pro-IL1 β , forming active IL1 β prior to its secretion [48].”
Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity
Veglia, F., Sanseviero, E., & Gabrilovich, D. I. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-020-00490-y · Cited by 1,940 · cited 1× · see citing works
“It is well described that there is an outgrowth of myeloid derived suppressor cells and that other myeloid cells polarize towards a “tumor-associated-like” phenotype in tumor bearing animals and humans [28].”
Macrophages as tools and targets in cancer therapy
Mantovani, A., Allavena, P., Marchesi, F., & Garlanda, C. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00520-5 · Cited by 1,807 · cited 1× · see citing works
“However, myeloid immune cells are required for antigen presentation and effective anti-tumor responses [7], so simple ablation strategies would have severe limitations.”
Guy, C. T., Cardiff, R., & Muller, W. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.3.954-961.1992 · Cited by 1,710 · cited 1× · see citing works
“As such, they develop ‘spontaneous’ mammary tumors reflective of human disease [30–32].”
Bile acids: regulation of synthesis
Chiang, J. Y. L. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r900010-jlr200 · Cited by 1,567 · cited 1× · see citing works
“When cholesterol is metabolized into bile acids [22], these serve as ligands for the farnesoid x receptor (FXR) which upregulates NR0B2 (small heterodimer partner; SHP).”
Regulatory T cells in cancer immunosuppression — implications for anticancer therapy
Togashi, Y., Shitara, K., & Nishikawa, H. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0175-7 · Cited by 1,553 · cited 2× · see citing works
“As they expand, a portion of CD4 + T cells differentiate into T regs , the amount being dependent on the strength of the activating signal, local cytokine milieu, contact with other (myeloid) cell types and several other factors [29].”
The cellular and molecular origin of tumor-associated macrophages
Franklin, R. A., Liao, W., Sarkar, A., Kim, M. V., Bivona, M. R., Liu, K., Pamer, E. G., & Li, M. O. (2014) · Science · doi:10.1126/science.1252510 · Cited by 1,399 · cited 1× · see citing works
“Tumor associated myeloid cells may be “educated” and behave differently than naïve BMDMs [17, 44].”
Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer
Schmid, P., Cortes, J., Dent, R., Pusztai, L., McArthur, H., Kümmel, S., Bergh, J., Denkert, C., Park, Y. H., Hui, R., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2112651 · Cited by 1,274 · see citing works
NLRP3 inflammasome in cancer and metabolic diseases
Sharma, B. R., & Kanneganti, T. (2021) · Nature Immunology · doi:10.1038/s41590-021-00886-5 · Cited by 1,112 · cited 2× · see citing works
“Several recent studies have shown the NLRP3 (NLR family pyrin domain-containing 3) inflammasome pathway to be strongly related to the development and metastasis of breast cancer [36–38].”
Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis
Song, X., Sun, X., Oh, S. F., Wu, M., Zhang, Y., Zheng, W., Geva-Zatorsky, N., Jupp, R., Mathis, D., Benoist, C., et al. (2020) · Nature · doi:10.1038/s41586-019-1865-0 · Cited by 1,024 · cited 1× · see citing works
“Downstream cholesterol homeostasis and bile acid signaling have also been implicated, with microbial transformed bile acids shown to alter T reg expansion in a T cell-intrinsic manner [56,57].”
Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism
Yang, W., Bai, Y., Xiong, Y., Zhang, J., Chen, S., Zheng, X., Meng, X., Li, L., Wang, J., Xu, C., et al. (2016) · Nature · doi:10.1038/nature17412 · Cited by 1,010 · cited 1× · see citing works
“Cholesterol itself plays important roles in myeloid and T cell biology, in addition to LXR activation [16,17,19, 52–54].”
Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells
Campbell, C., McKenney, P. T., Konstantinovsky, D., Isaeva, O. I., Schizas, M., Verter, J., Mai, C., Jin, W.-B., Guo, C.-J., Violante, S., et al. (2020) · Nature · doi:10.1038/s41586-020-2193-0 · Cited by 901 · see citing works
27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology
Nelson, E. R., Wardell, S., Jasper, J. S., Park, S., Suchindran, S., Howe, M. K., Carver, N. J., Pillai, R. V., Sullivan, P., Sondhi, V., et al. (2013) · Science · doi:10.1126/science.1241908 · Cited by 805 · cited 2× · see citing works
“The effects of 27HC on myeloid immune cells have been attributed to its ability to selectively modulate liver x receptors (LXRs), major regulators of cholesterol homeostasis [14,16,17].”
Self-citationLXR signaling couples sterol metabolism to proliferation in the acquired immune response
Bensinger, S. J., Bradley, M. N., Joseph, S. B., Zelcer, N., Janssen, E. M., Hausner, M. A., Shih, R., Parks, J. S., Edwards, P. A., Jamieson, B. D., et al. (2008) · Cell · doi:10.1016/j.cell.2008.04.052 · Cited by 711 · see citing works
Bunt, S. K., Yang, L.-L., Sinha, P., Clements, V., Leips, J., & Ostrand-Rosenberg, S. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-2354 · Cited by 680 · cited 1× · see citing works
“In primary and metastatic mammary tumors, IL1 signaling has been shown to be associated with increased infiltration of myeloid derived suppressor cells (MDSCs) in the tumor microenvironment, supporting an immune-suppressive environment [39].”
Blevins, H. M., Xu, Y., Biby, S., & Zhang, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.879021 · Cited by 587 · cited 1× · see citing works
“After NRLP3 oligomerization, it activates caspase 1 [43].”
Duan, Y., Gong, K., Xu, S., Zhang, F., Meng, X., & Han, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01125-5 · Cited by 538 · cited 1× · see citing works
“…forms a complex with SREBP cleavage activating protein (SCAP) in response to elevated oxysterol cholesterol metabolites, thereby regulating the synthesis of cholesterol and fatty acids through the prudent control of multiple genes associated with cholesterol biosynthesis and uptake [18,19].”
LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis.
Fayard, E., Auwerx, J., & Schoonjans, K. (2004) · Trends in Cell Biology · doi:10.1016/j.tcb.2004.03.008 · Cited by 445 · cited 1× · see citing works
“LXR and Liver Homologue Receptor-1 upregulate several genes associated with cholesterol catabolism and efflux [20, 21].”
Baek, A. E., Yu, Y.-R. A., He, S., Wardell, S. E., Chang, C.-Y., Kwon, S., Pillai, R. V., McDowell, H. B., Thompson, J. W., Dubois, L. G., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00910-z · Cited by 427 · cited 2× · see citing works
“In this regard, our preclinical work has demonstrated that mice on a high cholesterol diet have increased tumor growth and metastatic burden [14,15].”
Self-citationKaplanov, I., Carmi, Y., Kornetsky, R., Shemesh, A., Shurin, G. V., Shurin, M., Dinarello, C., Voronov, E., & Apte, R. (2018) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1812266115 · Cited by 404 · cited 2× · see citing works
“Several recent studies have shown the NLRP3 (NLR family pyrin domain-containing 3) inflammasome pathway to be strongly related to the development and metastasis of breast cancer [36–38].”
Yu, Y.-R., O’Koren, E. G., Hotten, D. F., Kan, M. J., Kopin, D., Nelson, E. R., Que, L., & Gunn, M. (2016) · PLoS ONE · doi:10.1371/journal.pone.0150606 · Cited by 343 · cited 1× · see citing works
“CD11C + cells are expected to be enriched with dendritic cells, although not exclusively [46,47].”
Self-citationTargeting inflammasome/IL-1 pathways for cancer immunotherapy
Guo, B., Fu, S., Zhang, J., Liu, B., & Li, Z. (2016) · Scientific Reports · doi:10.1038/srep36107 · Cited by 302 · cited 1× · see citing works
“Deficiency in NLRP3 or casp-1 in murine models of E0771 mammary cancer resulted in reduced lung metastasis [36,37].”
Simard, J.-C., Césaro, A., Chapeton-Montes, J. A., Tardif, M. R., Antoine, F., Girard, D., & Tessier, P. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072138 · Cited by 263 · cited 1× · see citing works
“Increased Ca 2+ works through S100A8 and A9 to increase reactive oxygen species (ROS) which then leads to NLRP3 assembly and activation [40].”
Role of nuclear receptor SHP in metabolism and cancer
Zhang, Y., Hagedorn, C. H., & Wang, L. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.10.006 · Cited by 235 · cited 1× · see citing works
“Previous reports have indicated a role for NR0B2 in hepatic carcinomas, but have largely focused on cancer-cell intrinsic roles [23,63–65].”
Immunotherapy for Breast Cancer: What Are We Missing?
Vonderheide, R. H., Domchek, S. M., & Clark, A. S. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-2569 · Cited by 233 · cited 1× · see citing works
“Although undoubtedly multifactorial, one major obstacle to immunotherapy is the immune-suppressive microenvironment of breast tumors maintained by myeloid immune cells and regulatory T cells (T regs ) [5,6].”
Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial
Bjarnadottir, O., Romero, Q., Bendahl, P.-O., Jirström, K., Rydén, L., Loman, N., Uhlén, M., Johannesson, H., Rose, C., Grabau, D., et al. (2013) · Breast Cancer Research and Treatment · doi:10.1007/s10549-013-2473-6 · Cited by 230 · cited 1× · see citing works
“However, a robust upregulation of HMGCoA-reductase, the enzymatic target of statins, was also observed [12,13].”
Interleukin-1 as Innate Mediator of T Cell Immunity
Eeckhout, B. V. D., Tavernier, J. H., & Gerlo, S. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.621931 · Cited by 211 · cited 1× · see citing works
“This was intriguing to us since a downstream executioner of the inflammasome, activated IL1, has previously been shown to (1) act as an innate-derived cytokine mediator of T cell immunity [33], and (2) increase T reg expansion in cocultures of CD4 + T cells with DCs [34,35].”
Brendel, C., Schoonjans, K., Botrugno, O. A., Treuter, E., & Auwerx, J. H. (2002) · Molecular Endocrinology · doi:10.1210/me.2001-0194 · Cited by 199 · cited 1× · see citing works
“Instead, it directly interacts with other proteins such as the LXRs to inhibit their activity and thus cholesterol catabolism [24].”
Yuk, J., Shin, D.-M., Lee, H. M., Kim, J. J., Kim, S.-W., Jin, H. S., Yang, C., Park, K. A., Chanda, D., Kim, D., et al. (2011) · Nature Immunology · doi:10.1038/ni.2064 · Cited by 188 · cited 1× · see citing works
“Mice with a whole-body knockout of NR0B2 were protected from septic shock induced by LPS [67].”
Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion
Tengesdal, I. W., Menon, D. R., Osborne, D. G., Neff, C., Powers, N. E., Gamboni, F., Mauro, A., D'Alessandro, A., Stefanoni, D., Henen, M., et al. (2021) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2000915118 · Cited by 166 · cited 2× · see citing works
“9A, [34,35,49]).”
Kwak, T., Wang, F., Deng, H., Condamine, T., Kumar, V., Perego, M., Kossenkov, A., Montaner, L., Xu, X.-W., Xu, W., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108571 · Cited by 158 · cited 1× · see citing works
“Interestingly, the mRNA expression of NR0B2 was decreased in bone marrow derived macrophages (BMDMs) derived from monocytic precursors of tumor bearing mice compared to tumor-naïve mice [26,27] (Fig.”
Checkpoint inhibitors in breast cancer – Current status
Dyhl-Polk, A., Svane, I. M., Andersson, M., & Nielsen, D. L. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.12.008 · Cited by 154 · cited 1× · see citing works
“However, even among this population, the majority of metastatic tumors do not respond to adjuvant α PD1 [3,4].”
Yang, C.-S., Kim, J.-J., Kim, T. S., Lee, P. Y., Kim, S. Y., Lee, H.-M., Shin, D., Nguyen, L. T., Lee, M., Jin, H. S., et al. (2015) · Nature Communications · doi:10.1038/ncomms7115 · Cited by 135 · cited 1× · see citing works
“Interestingly, NR0B2 was previously found to directly interact with NLRP3 to attenuate the NLRP3 inflammasome [66].”
Nelson, E. R., DuSell, C. D., Wang, X., Howe, M. K., Evans, G., Michalek, R. D., Umetani, M., Rathmell, J., Khosla, S., Gesty‐Palmer, D., et al. (2011) · Endocrinology · doi:10.1210/en.2011-1298 · Cited by 122 · cited 1× · see citing works
“Cell proliferation was assessed by staining for total DNA with Hoechst 33342 dye, similar to previously reported [68,69].”
Self-citationZhang, Y.-X., Xu, P., Park, K., Choi, Y., Moore, D. D., & Wang, L. (2008) · Hepatology · doi:10.1002/hep.22342 · Cited by 118 · see citing works
Immunotherapy in breast cancer: Current status and future directions
(2019) · Advances in Cancer Research · doi:10.1016/bs.acr.2019.03.006 · Cited by 109 · cited 1× · see citing works
“Although undoubtedly multifactorial, one major obstacle to immunotherapy is the immune-suppressive microenvironment of breast tumors maintained by myeloid immune cells and regulatory T cells (T regs ) [5,6].”
Immune Checkpoint Blockade for Breast Cancer
Swoboda, A., & Nanda, R. (2018) · Cancer treatment and research · doi:10.1007/978-3-319-70197-4_10 · Cited by 101 · cited 1× · see citing works
“However, even among this population, the majority of metastatic tumors do not respond to adjuvant α PD1 [3,4].”
Ma, L., Wang, L., Nelson, A. T., Han, C., He, S., Henn, M. A., Menon, K., Chen, J. J., Baek, A. E., Vardanyan, A., et al. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.08.020 · Cited by 98 · cited 7× · see citing works
“Cholesterol metabolites shift myeloid cells to being highly immune suppressive, in part through LXR activation [16,51,55].”
InfluentialSelf-citationElliott, J., Rougé, L., Wiesmann, C., & Scheer, J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806121200 · Cited by 85 · cited 1× · see citing works
“While these observations were interesting in the context of mRNA regulation by NR0B2, since caspase 1 is normally in an inactive zymogen form, being activated when assembled into the inflammasome complex [45].”
Oxysterols and nuclear receptors
Ma, L., & Nelson, E. R. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2019.01.016 · Cited by 81 · cited 1× · see citing works
“Cholesterol itself plays important roles in myeloid and T cell biology, in addition to LXR activation [16,17,19, 52–54].”
Self-citationSerum Lipids and Outcome of Early-stage Breast Cancer: Results of a Prospective Cohort Study
Bahl, M., Ennis, M., Tannock, I. F., Hux, J. E., Pritchard, K. I., Koo, J., & Goodwin, P. J. (2005) · Breast Cancer Research and Treatment · doi:10.1007/s10549-005-6654-9 · Cited by 80 · cited 1× · see citing works
“Clinical observations have identified an association between hypercholesterolemia and breast cancer recurrence [8].”
The Significance of Cholesterol and its Metabolite, 27-Hydroxycholesterol in Breast Cancer
Nelson, E. R. (2017) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2017.09.021 · Cited by 74 · cited 1× · see citing works
“On the other hand, large retrospective studies have now shown that patients taking cholesterol lowering medication (inhibitors of 2-hydroxy-3-methylglutaryl coenzyme A reductase; HMGCR; statins) demonstrate a significantly increased time to breast cancer recurrence [9].”
Self-citationKim, Y.-C., Seok, S., Zhang, Y., Ma, J., Kong, B., Guo, G. L., Kemper, B., & Kemper, J. (2020) · Nature Communications · doi:10.1038/s41467-020-19803-9 · Cited by 73 · cited 1× · see citing works
“Emerging reports indicate roles outside this axis as well as extra-hepatic roles [59–62].”
The Contribution of Cholesterol and its Metabolites to the Pathophysiology of Breast Cancer
Baek, A., & Nelson, E. R. (2016) · Hormones & cancer · doi:10.1007/s12672-016-0262-5 · Cited by 66 · cited 1× · see citing works
“LXR and Liver Homologue Receptor-1 upregulate several genes associated with cholesterol catabolism and efflux [20, 21].”
Self-citationAssociation of statin use with clinical outcomes in patients with triple‐negative breast cancer
Nowakowska, M. K., Lei, X., Thompson, M. T., Shaitelman, S. F., Wehner, M. R., Woodward, W. A., Giordano, S. H., & Nead, K. T. (2021) · Cancer · doi:10.1002/cncr.33797 · Cited by 62 · cited 1× · see citing works
“Recent studies found that statins were associated with improved breast cancer specific and overall survival in TNBC patients [10,11].”
Global Transcriptional Changes Following Statin Treatment in Breast Cancer
Bjarnadóttir, Ó., Kimbung, S., Johansson, I., Veerla, S., Jönsson, M., Bendahl, P., Grabau, D., Hedenfalk, I., & Borgquist, S. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-1403 · Cited by 59 · cited 1× · see citing works
“However, a robust upregulation of HMGCoA-reductase, the enzymatic target of statins, was also observed [12,13].”
Kim, Y. S., Han, C.-Y., Kim, S., Kim, J., Lee, S., Jung, D.-J., Park, S. Y., Kang, H., Choi, H., Lee, J. W., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101977200 · Cited by 54 · see citing works
Our evolving understanding of how 27-hydroxycholesterol influences cancer
Ma, L., Cho, W., & Nelson, E. R. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114621 · Cited by 53 · cited 1× · see citing works
“Cholesterol metabolites shift myeloid cells to being highly immune suppressive, in part through LXR activation [16,51,55].”
Self-citationHost CYP27A1 expression is essential for ovarian cancer progression.
He, S.-S., Ma, L., Baek, A., Vardanyan, A., Vembar, V., Chen, J. J., Nelson, A. T., Burdette, J. E., & Nelson, E. R. (2019) · Endocrine-Related Cancer · doi:10.1530/erc-18-0572 · Cited by 49 · cited 1× · see citing works
“Interestingly, the mRNA expression of NR0B2 was decreased in bone marrow derived macrophages (BMDMs) derived from monocytic precursors of tumor bearing mice compared to tumor-naïve mice [26,27] (Fig.”
Self-citationNuclear receptors, cholesterol homeostasis and the immune system
Shahoei, S. H., & Nelson, E. R. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.04.013 · Cited by 43 · cited 5× · see citing works
“NR0B2 is best known as a regulator of cholesterol and bile acid homeostasis, directly binding and inhibiting LXR and LRH-1 mediated induction of cholesterol catabolism and efflux [23].”
InfluentialSelf-citationBaek, A. E., Krawczynska, N., Das Gupta, A., Dvoretskiy, S. V., You, S., Park, J., Deng, Y.-H., Sorrells, J. E., Smith, B. P., Ma, L., et al. (2021) · Endocrinology · doi:10.1210/endocr/bqab095 · Cited by 43 · cited 1× · see citing works
“This models colonization and lesion outgrowth in a common metastatic site (primarily lung) [16,50,51].”
Self-citationFXR mediates T cell-intrinsic responses to reduced feeding during infection
Campbell, C., Marchildon, F., Michaels, A. J., Takemoto, N., van der Veeken, J., Schizas, M., Pritykin, Y., Leslie, C., Intlekofer, A., Cohen, P., et al. (2020) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2020619117 · Cited by 41 · cited 1× · see citing works
“There is some evidence that these effects are mediated through the bile acid receptors Farnesoid X Receptor (FXR) or TGR5 [56,58], but this still requires further investigation.”
Impact of Statin Use on Outcomes in Triple Negative Breast Cancer
Shaitelman, S., Stauder, M., Allen, P., Reddy, S., Lakoski, S., Atkinson, B., Reddy, J., Amaya, D., Guerra, W., Ueno, N., et al. (2017) · Journal of Cancer · doi:10.7150/jca.18743 · Cited by 40 · cited 1× · see citing works
“Recent studies found that statins were associated with improved breast cancer specific and overall survival in TNBC patients [10,11].”
Brinster, C., & Shevach, E. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0208085 · Cited by 34 · cited 2×
“9A, [34,35,49]).”
Heys, S., Stewart, K., McKenzie, E., Miller, I., Wong, S. Y. C., Sellar, G., & Rees, A. (2012) · Breast Cancer Research and Treatment · doi:10.1007/s10549-012-2190-6 · Cited by 32 · cited 1× · see citing works
“CD11C + cells are expected to be enriched with dendritic cells, although not exclusively [46,47].”
Nelson, E. R., & Habibi, H. (2008) · Endocrinology · doi:10.1210/en.2008-0107 · Cited by 28 · cited 2× · see citing works
“All transfections were conducted in accordance with the manufacturer’s protocol and similar to previous work [69,70].”
Self-citationIL-1β Promotes TGF-β1 and IL-2 Dependent Foxp3 Expression in Regulatory T Cells
Ganesh, B. B., Bhattacharya, P., Gopisetty, A., Sheng, J., Vasu, C., & Prabhakar, B. S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021949 · Cited by 27 · see citing works
Nuclear Receptor Small Heterodimer Partner in Apoptosis Signaling and Liver Cancer
Zhang, Y.-X., & Wang, L. (2011) · Cancers · doi:10.3390/cancers3010198 · Cited by 25 · cited 1× · see citing works
“Previous reports have indicated a role for NR0B2 in hepatic carcinomas, but have largely focused on cancer-cell intrinsic roles [23,63–65].”
Ma, L., Vidana Gamage, H. E., Tiwari, S., Han, C., Henn, M. A., Krawczynska, N., Dibaeinia, P., Koelwyn, G. J., Das Gupta, A., Bautista Rivas, R. O., et al. (2022) · Endocrinology · doi:10.1210/endocr/bqac072 · Cited by 21 · cited 4× · see citing works
“The effects of 27HC on myeloid immune cells have been attributed to its ability to selectively modulate liver x receptors (LXRs), major regulators of cholesterol homeostasis [14,16,17].”
InfluentialSelf-citationFeeding activates FGF15‐SHP‐TFEB‐mediated lipophagy in the gut
Seok, S., Kim, Y., Zhang, Y., Kong, B., Guo, G. L., Ma, J., KEMPER, B. W., & Kemper, J. K. (2022) · The EMBO Journal · doi:10.15252/embj.2021109997 · Cited by 20 · see citing works
Small Heterodimer Partner Regulates Dichotomous T Cell Expansion by Macrophages
Shahoei, S. H., Kim, Y.-C., Cler, S. J., Ma, L., Anakk, S., Kemper, J. K., & Nelson, E. R. (2019) · Endocrinology · doi:10.1210/en.2019-00025 · Cited by 16 · cited 8× · see citing works
“…confirm earlier findings that NR0B2 in bone marrow derived macrophages (BMDMs) acts to skew T cell expansion away from regulatory T cells (T regs ) [25], and expand these findings to show that NR0B2 within several different myeloid immune cell types, including tumor associated ones, acts to…”
InfluentialSelf-citationThe nuclear receptor TLX (NR2E1) inhibits growth and progression of triple- negative breast cancer
Nelczyk, A. T., Ma, L., Gupta, A. D., Gamage, H. E. V., McHenry, M. T., Henn, M. A., Kadiri, M., Wang, Y., Krawczyńska, N., Bendre, S. V., et al. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166515 · Cited by 15 · cited 4× · see citing works
“Cell proliferation was assessed by staining for total DNA with Hoechst 33342 dye, similar to previously reported [68,69].”
InfluentialSelf-citationDeletion of intestinal SHP impairs short-term response to cholic acid challenge in male mice.
Nguyen, J. T., Riessen, R., Zhang, T., Kieffer, C., & Anakk, S. (2021) · Endocrinology · doi:10.1210/endocr/bqab063 · Cited by 14 · cited 1× · see citing works
“Emerging reports indicate roles outside this axis as well as extra-hepatic roles [59–62].”
Shaw, R., Kolyvas, P., Dang, N., Hyon, A., Bailey, K., & Anakk, S. (2022) · Endocrinology · doi:10.1210/endocr/bqac052 · Cited by 8 · see citing works
Flagged first, then by citations
2 of the 66 references couldn’t be matched to a known paper.
Research works printed but not linked: 5
- [31]Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW, Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases, Am. J. Pathol. 163 (2003) 2113– 2126. 14578209 PMC1892434
- [32]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
- [41]Cavallo-Medved D, Moin K, Sloane B, Cathepsin B: Basis Sequence: Mouse, AFCS Nat Mol Pages, 2011, p. 2011. PMC5541861 28781583
- [51]Baek AE, Yu Y-RA, He S, Wardell SE, Chang C-Y, 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
- [55]Ma L, Cho W, Nelson ER, Our evolving understanding of how 27-hydroxycholesterol influences cancer, Biochem. Pharmacol. (2021) 114621. 34043965 PMC8611110
Cited by
Sorted by citations
Cholesterol metabolism in tumor immunity: Mechanisms and therapeutic opportunities for cancer
Guo, X., Zhu, B., Li, J., Guo, P., Niu, Y., Shi, J., Yokoyama, W., Huang, Q., & Shao, D. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116802 · Cited by 23 · see citing works
Inflammasomes and pyroptosis in cancer: mechanisms and therapeutic advances
Seo, W., Jung, B., Roh, T., Shin, H. J., Song, I.-C., Chung, C., & Jo, E. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-025-01763-6 · Cited by 18 · see citing works
“By re-educating these cells, NR0B2 suppresses the expansion of regulatory T cells, thereby reducing tumor growth and improving treatment efficacy in metastatic breast cancer [225].”
Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells
Bendre, S. V., Wang, Y., Hajyousif, B., K C, R., Bhogale, S. G., Pradeep, D., Krawczynska, N., Schane, C. P., Weisser, E., Singh, A., et al. (2026) · Science Advances · doi:10.1126/sciadv.adx5490 · Cited by 8 · see citing works
“The negative regulator of cholesterol catabolism, NR0B2, was found to suppress several aspects of the inflammasome in MCs, resulting in decreased expansion of regulatory T cells (T reg cells) ( 26 , 27 ).”
Self-citationZhang, H., Liang, Y., Deng, S.-Y., & Du, J. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.101851 · Cited by 2 · see citing works
“NR0B2 affects tumor immunotherapy by suppressing tumor-associated metabolic reprogramming, reducing inflammatory responses in the tumor microenvironment, enhancing effector T cell activity, and inhibiting Treg function [50].”
Cholesterol efflux protein, ABCA1, supports anti-cancer functions of myeloid immune cells
Bendre, S. V., Wang, Y., Hajyousif, B., Rajendra, K., Bhogale, S. G., Pradeep, D., Krawczynska, N., Schane, C. P., Weisser, E., Singh, A., et al. (2025) · bioRxiv · doi:10.1101/2025.02.19.638515 · Cited by 2
“The negative regulator of cholesterol catabolism, NR0B2, was found to suppress several aspects of the inflammasome in myeloid cells, resulting in decreased expansion of regulatory T cells (Tregs) (24, 25).”
Self-citationLRH-1 is a novel regulator of neutrophil-driven immune responses within the tumor microenvironment
Wang, Y., Duong, B., Keeley, S., Krawczyńska, N., Bendre, S. V., Schane, C. P., Pradeep, D., Rodriguez-Casiano, D., Weisser, E., Vuilleumier, N. C., et al. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218910 · Cited by 1 · see citing works
Self-citationXu, F.-Y., Lee, W., Shi, K.-C., Saha, U., Cui, Y.-X., James, S., Medina, N. Y. G., Nelson, E. R., & Smith, A. M. (2026) · Bioconjugate chemistry · doi:10.1021/acs.bioconjchem.6c00251
Self-citationFan, Z.-Z., Wang, N., Zhang, B., Deng, K.-Y., Fu, J.-J., Ma, L., Li, J.-Y., Xu, Z.-F., & Guo, Y. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03933-w
“In addition, persistent IL-1β signaling promotes the expansion of MDSCs and M2 TAMs and further suppresses CD8 ⁺ T cell function through the secretion of IL-10, TGF-β, and ARG1, thereby forming a positive feedback immunosuppressive circuit [120, 121].”
Self-citationSchane, C. P., Nelczyk, A. T., Chen, C., Seo, J., Wang, Y., Krawczyńska, N., Bendre, S. V., Weisser, E., Pradeep, D., Gamage, H. E. V., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.14.718388
Self-citationLRH-1 is a novel regulator of neutrophil-driven immune responses within the tumor microenvironmentPreprint
Wang, Y., Duong, B., Keeley, S., Krawczynska, N., Bendre, S. V., Schane, C. P., Weisser, E., Cobo-Vuilleumier, N., Kockaya, L. I., Fei, Y.-F., et al. (2025) · bioRxiv · doi:10.1101/2025.09.16.676030
“By doing so, it decreases the ability of these cells to support the expansion of regulatory T cells (T regs ) – a cell type that is highly immune-suppressive (16,17).”
Self-citation
- Authors
- Vidana Gamage, H. E., Shahoei, S. H., Wang, Y., Jacquin, E., Weisser, E., Bautista, R. O., Henn, M. A., Schane, C. P., Nelczyk, A. T., Ma, L., Das Gupta, A., Bendre, S. V., Nguyen, T., Tiwari, S., Tjoanda, E., Krawczynska, N., He, S., Albright, S. T., Farmer, R., Smith, A. J., Fink, E. C., Chen, H., Sverdlov, M., Gann, P. H., Boidot, R., Vegran, F., Fanning, S. W., Hergenrother, P. J., Apetoh, L., & Nelson, E. R.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Loyola University Chicago (US)
- University of Illinois Chicago (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Nelson, Erik R.
- ORCID
- Vidana Gamage, Hashni Epa
- Shahoei, Sayyed Hamed
- Wang, Yu
- Jacquin, Elise
- Weisser, Erin
- Schane, Claire P.
- Nelczyk, Adam T.
- Ma, Liqian
- Das Gupta, Anasuya
- Bendre, Shruti V.
- Krawczynska, Natalia
- He, Sisi
- Smith, Amanda J.
- Fink, Emma C.
- Chen, Hong
- Sverdlov, Maria
- Gann, Peter H.
- Boidot, Romain
- Fanning, Sean W.
- Hergenrother, Paul J.
- Apetoh, Lionel
- Nelson, Erik R.
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2024-08
- Volume
- 597
- Pages
- 217042
- ISSN
- 0304-3835 (ISSN-L)
- PMC
- PMC11892351
- OpenAlex
- W4399852252
- Cited by
- 9
- References
- 66
- Citations by year
- 2026: 5 · 2025: 4
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Letters (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Defense (W81XWH, BC200206/W81XWH-20-BCRP-EOHS)
- Agence Nationale de la Recherche (ANR-11-LABX-0021)
- National Institutes of Health (W81XWH)
- University of Illinois at Urbana-Champaign
- National Cancer Institute (R01CA234025)
- National Institute of General Medical Sciences (T32GM136629)
- National Institute of Environmental Health Sciences (T32ES007326)
- National Institute of Biomedical Imaging and Bioengineering (T32EB019944)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- NR0B2, myeloid cells, regulatory T cells, tumor immunosuppression, cholesterol metabolism, inflammasome, IL-1β, breast cancer, solid tumors, immune checkpoint blockade, tumor growth, therapeutic target
- MeSH terms
- Animals, Breast Neoplasms, Female, Humans, Mice, Knockout, Disease Progression, Myeloid Cells, Cell Line, Tumor, Cell Proliferation, T-Lymphocytes, Regulatory, Mice, Interleukin-1beta, Inflammasomes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
