Abstract 394: LXR agonist N,N-dimethyl-3-β-hydroxy-cholenamide, DMHCA, reduces ErbB2-dependent tumorigenesis and immune tolerance in a conditional model of mammary fibrosis

Background: One of the central challenges for cancer therapy is the identification of factors in the tumor microenvironment that increase tumor progression and prevent the immune system from eradicating the tumor. One such factor associated with breast cancer is stromal fibrosis, a histopathologic criterion for invasive cancer and poor survival. Fibrosis is caused by inflammatory factors and remodeling of the extracellular matrix, which results in excessive collagen deposition and an immune tolerant environment. Experimental Procedures: We developed a novel transgenic model representative of HER2/ErbB2+ breast cancer, termed NeuT/ATTAC, in which partial ablation of mammary fat resulted in its replacement with fibrotic tissue. NeuT/ATTAC mice were administered a diet supplemented with 0.04% DMHCA, a desmosterol-like pan agonist of the liver X receptor (LXR). Collagen deposition resulting from fibrosis was assessed by second harmonic generation (SHG) fluorescence microscopy and histological staining, immune cell subsets were analyzed by fluorescence-activated cell sorting and biomarkers of fibrosis, proliferation and immune tolerance were determined by IHC. Findings: Administration of DMHCA to NeuT/ATTAC mice beginning at two months of age reduced tumorigenesis, tumor multiplicity and suppressed fibrosis as shown by loss of collagen, fibroblast activation protein (FAP) and α-smooth muscle actin (SMA). These changes were accompanied by a marked reduction in the percentage of MDSC, and an increase in CD8+ effector T cells and PD1+/Foxp3+ CD4 T cells. Conclusion: Reduction of fibrosis, tumorigenesis and immune tolerance by DMHCA suggests that this LXR agonist may be useful for reducing tumor-associated fibrosis and in combination with immune checkpoint inhibitors that target PD1+ Treg cells for moderating immune tolerance. Unlike non-steroidal LXR agonists, DMHCA does not increase serum triglycerides or produce hepatic steatosis, and may therefore be a good candidate for clinical studies. Supported by a Sher Award, 1P30CA051008 from the NCI, NIH, to the Lombardi Comprehensive Cancer Center, and R01 HL133545 and R01 DK116567 from the NIH to M.L. Citation Format: Robert I. Glazer, Gao Sheng, Hongyan Yuan, Suman Ranjit, Jin Lu, Xun Lu, Moshe Levi. LXR agonist N,N-dimethyl-3-β-hydroxy-cholenamide, DMHCA, reduces ErbB2-dependent tumorigenesis and immune tolerance in a conditional model of mammary fibrosis [abstract]. In: Proceedings of the Annual Meeting of the Amer