OR05-01 Myeloid Cell Intrinsic NR0B2 Inhibits Regulatory T Cell Expansion Within The Tumor Microenvironment: Potential Novel Strategy For Breast Cancer Immunotherapy
Authors: Vidana Gamage Hashni Epa , Shahoei Sayyed Hamed , Albright Samuel , Nguyen Tiffany , Farmer Rachel Elizabeth , Weisser Erin , Bautista Rivas Rafael Ovidio , Schane Claire P , Wang Yu , Nelczyk Adam , Ma Liqian , Tiwari Srishti , Gupta Anasuya Das , Bendre Shruti , Apetoh Lionel , Hergenrother Paul , Nelson Erik Russell 
Published: October 2023

Disclosure: H. Vidana Gamage: None. S. Shahoei: None. S. Albright: None. T. Nguyen: None. R. Farmer: None. E. Weisser: None. R. Bautista Rivas: None. C.P. Schane: None. Y. Wang: None. A. Nelczyk: None. L. Ma: None. S. Tiwari: None. A. Das Gupta: None. S. Bendre: None. L. Apetoh: None. P. Hergenrother: None. E.R. Nelson: None.

Breast cancer remains the second leading cause of cancer-related death in women. Immune-oncology interventions for the treatment of breast cancer have thus far been underwhelming, providing strong rationale for the development of drugs to increase their efficacy. A major obstacle to immunotherapy is the highly immunosuppressive tumor microenvironment. This phenomenon is strongly maintained by myeloid cells and regulatory T cells (Tregs), which are associated with immune escape, poor prognosis and treatment resistance. Importantly, myeloid cells are also critical for a robust anti-tumor response. Therefore, we require strategies to re-educate myeloid cells rather than eliminating them. Elevated cholesterol is a risk factor for breast cancer, while cholesterol-lowering drugs are associated with a good prognosis. Previous work has demonstrated that certain downstream metabolites of cholesterol, can promote immune escape and metastatic progression. The nuclear receptor NR0B2 is a critical negative regulator of cholesterol homeostasis. Mining clinical data, we have found that high tumoral expression of NR0B2 is associated with an increased time to recurrence. Single cell RNA-sequencing indicates that NR0B2 is expressed within the myeloid cells of normal breast tissue. Thus, we hypothesized that myeloid cell NR0B2 is involved in breast cancer pathophysiology and can be used as a druggable target. Intriguingly, overexpression of NR0B2 or activation with a small molecule agonist in murine bone marrow derived macrophages (BMDMs) or dendritic cells skewed T cell expansion away from Tregs. Conversely, Treg expansion increased when NR0B2 was knocked down. In order to investigate the role of NR0B2 in vivo, we monitored the growth of tumors grafted into mice that had NR0B2 genetically knocked out in the myeloid lineage (NR0B2fl/fl;LysMCre+) and respective control mice (NR0B2wt/wt;LysMCre+). Mice lacking NR0B2 exhibited significantly increased tumor growth and elevated tumor infiltrating Tregs. Additionally, human breast tumors samples indicated an inverse correlation between NR0B2 and FOXP3 (marker for Tregs). We further investigated the downstream targets of NR0B2 mediating this anti-tumor phenotype and identified that NLRP3 inflammasome-IL1β axis 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 therapy. 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 strategy to improve breast cancer immunotherapy.

Presentation: Thursday, June 15, 2023