Breast cancer (BC) was considered an immunologically silent tumor, however recent findings suggest that immune cells present in the tumor microenvironment play important roles in tumor growth. Retinoid X receptors (RXRs) are a subclass of nuclear receptors that act as ligand-dependent transcription factors that regulate a variety of cellular processes including proliferation and differentiation. Rexinoids are synthetic molecules that bind and activate RXRs. Bexarotene (Targretin®) is the only rexinoid approved by the FDA and is used for the treatment of refractory cutaneous T-cell lymphoma. Other more potent rexinoids have been synthesized, such as LG100268 and LG101506, which will not be tested in clinical trials because of intellectual property issues. Because recent studies have suggested that RXRs are involved in immune regulation, we synthesized novel rexinoids and selected MSU-42011 as a lead compound. MMTV-neu mice with tumors approximately 32 mm3 in volume were treated with control diet or MSU-42011 (100 mg/kg diet) for 10 days. Rexinoid treatment significantly (p=0.0069) reduced tumor fold change normalized to initial volume from 8.33 in controls to 4.80 on treatment. Analysis of the tumor by flow cytometry showed no significant differences in the major immune populations, such as T cells, macrophages and dendritic cells. However, expression of PDL1 was increased in CD11c+, MHC-II+ dendritic cells (5484 vs 7140 MFI, p=0.0456), suggesting engaged dendritic cells in activating cytotoxic T cells. To further elucidate the cross talk between dendritic and T cells, cytokines associated with T cell recruitment and activation were analyzed by RT-PCR. Tumor treated with MSU42011 had a 38.5 fold increase in IL12a expression (p=0.011, n=4), and a 20.8 fold increase in CCL9 (p=ns, n=4), suggesting that dendritic cells are actively recruiting and activating T cells. The activation of cytotoxic T cells was confirmed by a 75.5 fold increase in interferon gamma (p=0.0026, n=4) and a decrease of FOXP3 expression (p=ns, n=4). To test if the effects seen in tumor reduction were dependent on the presence of T cells, CD4 and CD8 were depleted. Depletion of CD4 alone, but not CD8, reversed the tumor reduction induced by MSU-42011. These results show that RXR agonists can be used to modulate immune cell populations in the tumor microenvironment, specifically by recruiting and activating dendritic cells that then activate cytotoxic T cells. We thank the Breast Cancer Research Foundation for support of these studies.
Citation Format: Ana Sofia Leal, Sarah Carapellucci, Karen T. Liby. The rexinoid MSU-42011 enhances dendritic-T cell cross talk in a HER2 positive model of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB134.