Expression data from Cysltr1 deficient bone marrow in vitro induced myeloid cells

In established cancer in mice and humans, “emergency” myelopoiesis usually occurs to facilitate malignancy progression. In particular, neutrophils and immature myeloid cells accumulated in the bone marrow, periphery and tumor are potent mediators of immunosuppression and tumor promotion. However, the molecular pathways regulating tumor-induced emergency myelopoiesis remain largely elusive. Here, we demonstrated that Cysteinyl leukotriene receptor 1 (CysLTR1), a key player for asthma, allergic rhinitis and other inflammatory conditons, was expressed selectively in myeloid cells from tumor-bearing hosts with the most significant expression in infiltrating immature neutrophils. Genetic ablation and pharmacological inhibition of CysLTR1 resulted in diminished tumor growth with enhanced antitumor immunity. The anti-tumor effect of CysLTR1 inhibition was linked with transcriptomic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor immune phenotype; this process required the distinct transcriptional factors to specifically dictate neutrophil progenitor commitment and differentiation in association with controlled degranulation. Furthermore, single-cell RNA sequencing analysis provided a comprehensive transcriptional landscape of neutrophil maturation, function and fate decision in tumor bearers, confirming a CysLTR1-dependent transcriptomic mechanism for fine-tuned regulation of tumor-induced emergency granulopoiesis. CysLTR1-mediated changes in the differentiation and degranulation also occurred in human neutrophils and correlated with the survival and immune checkpoint therapy responsiveness in cancer patients. Consistently, targeting CysLTR1 with clinically available antagonists overcame resistance to immune checkpoint PD-1 inhibitors in several mouse tumor models. These findings thus have important implications for understanding the abnormal myelopoiesis during cancer progression and suggest new therapeutic approaches to improve immune checkpoint blockade.