The distinct role of cysteinyl leukotriene receptor for myeloid-derived suppressive cells

Myeloid-derived suppressor cells (MDSCs) accumulate in the blood, lymph nodes, and bone marrow and at tumor sites in most patients and animals with cancer suppress antitumor immunity and are therefore a significant impediment to cancer immunotherapy. Given the nature of cellular heterogeneity and plasticity of MDSCs, the mechanisms and in situ conditions that regulate and sustain MDSC differentiation and survival, and the mechanisms MDSC use to promote tumor progression remain largely unknown. Our preliminary data demonstrate the importance of type 1 cysteinyl leukotriene receptor (CysLTR1) for the accumulation and immunoregulatory activity of MDSCs in the cysteinyl leukotrienes (CysLTs)-rich tumor microenvironment. These results have led to the novel hypothesis that CysLTR1 signaling is essential in tumor-induced MDSC accumulation for both immune suppression and tumor promotion. In this proposal, we will characterize further the phenotype and function of MDSCs in the tumor microenvironment, and explore the signaling pathways implicated by CysLTR1 in regulating MDSC differentiation, turnover and function using both gain-of-function and loss-of-function approaches. Our research will provide new insights into how MDSCs are induced and suppress antitumor immunity, and how they are molded by the tumor microenvironment and may offer a clinically applicable strategy on MDSC targeting to enhance the efficacy of current tumor immunotherapies. Our specific Aims: Aim 1. Define the role of CysLTR1 in regulating accumulation and function of tumor-infiltrating MDSCs. 1.1 To determine whether CysLTR1 regulates the turnover, differentiation and migration of MDSCs. 1.2 To determine whether CysLTR1 regulates the suppressive activity and polarization of MDSCs. 1.3 To determine whether CysLTR1 regulates the suppressive activity and differentiation of human melanoma cell line-induced MDSCs. 1.4 To measure expression of CysLTR1 and MDSC-associated markers in human lung cancer and melanoma tissues. Aim 2. Determine whether CysLTR1 is required for critical transcriptional regulation of MDSCs. 2.1 To determine whether CyLTR1 activation regulates MDSC activity through PLC-PKC and C/EBPβ signalin. 2.2 To determine whether CysLTR1 activation regulates MDSC activity through Nrf2 signaling. Aim 3. Determine whether CysLTR1 on MDSCs is a central mediator of tumor-Induced immune suppression and tumor promotion. 3.1 To determine whether CysLTR1 orchestrates MDSCs and other important myeloid cell populations in tumor immune evasion. 3.2 To define the efficacy of combination therapy using CysLTR1 antagonists and anti-PD-1 and/or anti-PD-L1.