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.
We have proposed a pivotal role of CysLTR1 in regulating tumor-induced MDSC accumulation for both immune suppression and promotion of tumor progression. Our work will not only advance current understandings of how inflammatory lipid mediators in the tumor microenvironment fine-tune emergency myelopoiesis during cancer progression, but will provide the basis for development of novel therapies targeting tumor-infiltrating MDSCs in human cancer.
