Dysregulation of cholesterol homeostasis is associated with many diseases such as cardiovascular disease and cancer. Liver x receptors (LXRs) are major upstream regulators of cholesterol homeostasis and are activated by endogenous cholesterol metabolites such as 27-hydroxycholesterol (27HC). LXR and various LXR ligands such as 27HC have been described to influence several extra-hepatic biological systems. However, disparate reports of LXR function have emerged, especially with respect to immunology and cancer biology. This would suggest that similar to steroid nuclear receptors, the LXR can be selectively modulated by different ligands. Here, we use RNA-sequencing of macrophages and single-cell RNA-sequencing of immune cells from metastasis bearing murine lungs, to provide evidence that LXR satisfies the two principles of selective nuclear receptor modulation: (1) different LXR ligands result in overlapping but distinct gene expression profiles within the same cell type, and (2) the same LXR ligands differentially regulate gene expression in a highly context-specific manner, depending on the cell or tissue type. The concept that the LXR can be selectively modulated provides the foundation for developing precision-pharmacology LXR ligands that are tailored to promote those activities that are desirable (pro-immune), but at the same time minimizing harmful side effects (such as elevated triglyceride levels).
Immune checkpoint blockade (ICB) has revolutionized cancer therapy but has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. We demonstrate that NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the NLRP3 inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Loss of NR0B2 increased mammary tumor growth and metastasis. Small molecule agonists, including one developed here, reduced Treg expansion, reduced metastatic growth and improved the efficacy of ICB. This work identifies NR0B2 as a target to re-educate myeloid immune cells providing proof-of-principle that this cholesterol-homeostasis axis may have utility in enhancing ICB.
Breast cancer remains the second leading cause of cancer-related deaths among women. In recent years, immunotherapy has been tremendously successful in some metastatic cancers such as melanoma. However, a majority of breast cancer patients do not benefit from existing immunotherapy treatments, leaving many with an unmet need. Although undoubtedly multifactorial, one major obstacle to anti-cancer therapies, is the highly immunosuppressive breast tumor microenvironment. This phenomenon is strongly maintained by myeloid immune cells and immunosuppressive regulatory T cells (Tregs), which hinder anti-tumor immunosurveillance and promote tumor progression. Thus, strategies to ‘re-educate’ myeloid cells to inhibit Tregs is a potentially promising anti-cancer strategy. Mining clinical data, we have found that elevated mRNA expression of the nuclear receptor, NR0B2 within breast tumors is associated with an increased time to recurrence. Single cell RNA-sequencing indicates that NR0B2 is expressed within the macrophage populations of normal breast tissue, and various dendritic cell (DC) types in PBMCs. Overexpression of NR0B2 or activation with a small molecule agonist in murine bone marrow derived macrophages (BMDMs) or DCs resulted in a dichotomous T cell expansion - away from Tregs. Conversely, Treg expansion increased when NR0B2 was knocked-down. Tumor growth was markedly increased in mice lacking myeloid specific NR0B2 expression. We further investigated the downstream targets of NR0B2 mediating this anti-tumor phenotype and identified that NLRP3 inflammasome-IL1β activity is a likely modulator in re-educating myeloid cell-Treg function. Importantly, a putative small molecule agonist decreased established metastatic lesions and increased the efficacy of αPD-L1. Subsequent medicinal chemistry was used to develop a novel NR0B2 agonist with strong anti-metastatic properties when used as a single agent in a preclinical mouse model. Collectively, our data implicates NR0B2 within myeloid cells as a modulator of Tregs, a cell population that has thus far been therapeutically intractable. Therefore, NR0B2 may prove to be a promising therapeutic target to reshape the tumor microenvironment and improve breast cancer immunotherapy. This work was supported by the Era of Hope Scholar Award from the Department of Defense Breast Cancer Research Program grant (BC200206), National Cancer Institute (R01CA234025), and NIH Chemistry-Biology Interface Training Grant (T32-GM136629). Citation Format: Hashni Epa Vidana Gamage, Sayyed Hamed Shahoei, Tiffany Nguyen, Rachel Farmer, Samuel Albright, Erin Weisser, Rafael O. Bautista, Claire P. Schane, Yu Wang, Adam Nelczyk, Liqian Ma, Srishti Tiwari, Anasuya Das Gupta, Shruti Bendre, Lionel Apetoh, Paul J. Hergenrother, Erik R. Nelson. NR0B2 re-educates myeloid cells within the tumor microenvironment: Potential novel strategy for breast cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2358.
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