Targeting CysLTR1 in triple negative breast cancer

Our specific Aims: Aim 1. To determine the role of CysLTR1 in regulating accumulation and function of tumor-infiltrating MDSCs. Aim 2. To determine whether CysLTR1 is required for critical transcriptional regulation of MDSCs. Aim 3. To determine the therapeutic efficacy of CysLTR1 inhibition in combination with anti-PD-1/PDL1 immunotherapy. Study Design: Using both transplantable 4T1/E0771 and genetically engineered MMTV-PyMT transgenic TNBC models together with human TNBC specimens, we will characterize the phenotype and function of MDSCs in the CysLTs-rich tumor microenvironment, and explore the signaling pathways implicated by CysLTR1 in regulating tumor-induced MDSC accumulation and function using both gain-of-function and lossof-function approaches. Finally, we will examine if targeting CysLTR1 using Montelukast could improve the efficacy of anti-PD-1/PD-L1 therapy. Significance and impact: These studies will substantially increase knowledge of CysLTs/CysLTR1 signaling governing the TNBC microenvironment via MDSCs to facilitate immune tolerance and permit tumor progression. The proposed project will thus have rapid translational implications for the exploration of CysLTR1 inhibitors alongside agents that stimulate CD8+ T cell activity, including the checkpoint blockade therapies that target PD-1 and PD-L1, which are both in clinical development in treating TNBC.