GSE169688
Inhibition of PGE2-EP2/EP4 signaling elicits anti-tumor immunity through reprograming of inflammatory myeloid cells and   suppression of mRegDC-Treg axis
The discovery of immune checkpoint inhibitor (ICI) has highlighted the clinical importance of immune evasion in cancer. However, only a fraction of cancer patients show response to ICI, raising a question on immune suppression mechanisms other than immune checkpoint. In this study, we examined the role of the lipid inflammatory mediator PGE2 in immune evasion of the ICI-insensitive Lewis Lung Carcinoma line 1 (LLC1) mouse model. Inhibition of PGE receptors, EP2 and EP4, significantly suppressed tumor growth through the modulation of host immune cells. Single cell RNA-sequencing analysis revealed that EP2/4 inhibition elicited anti-tumor immunity through the reprogramming of inflammatory myeloid cells by downregulating expression of genes in NF?B signaling and actions and suppression of the mregDC-regulatory T cell axis by downregulating genes associated with regulatory T cell recruitment and activation. Taken together, our work suggests that PGE2-EP2/EP4 signaling induces proinflammatory myeloid and tolerogenic lymphoid environments in ICI-insensitive tumors, which is amenable to EP2 and EP4 inhibitors.. Overall design: Using 10x genomics to measure single-cell RNA sequence (scRNA-seq) to comprehensively characterize the tumor immune microenvironment in mouse LLC1 tumor syngeneic transplantation model from EP2 and EP4 antagonists treatment and Treg depletion.