Abstract 2358: NR0B2 re-educates myeloid cells within the tumor microenvironment: Potential novel strategy for breast cancer immunotherapy
Authors: Gamage Hashni Epa Vidana , Shahoei Sayyed Hamed , Nguyen Tiffany , Farmer Rachel , Albright Samuel , Weisser Erin , Bautista Rafael O. , Schane Claire P. , Wang Yu , Nelczyk Adam , Ma Liqian , Tiwari Srishti , Gupta Anasuya Das , Bendre Shruti , Apetoh Lionel , Hergenrother Paul J. , Nelson Erik R. 
Published: April 2023

Abstract
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.