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Dryad

MHC-II+ macrophage differentiation is impaired in metastasized lungs via PGE2 receptor EP2

Abstract

Monocytes differentiate into macrophages (Mφs) to facilitate lung metastasis, but the monocyte-to-Mφ transition during this process is not well understood. To investigate, we performed bulk RNA sequencing on Mφs isolated from the lungs of mice bearing Lewis lung carcinoma tumors and from naive lungs. Our results showed impaired differentiation of monocytes into MHC-II+ Mφ, with upregulation of PGE2-inducible genes, including Arg1, in tumor-associated Mφs (TAMs). In vitro experiments confirmed that PGE2 inhibits the differentiation of MHC-II+ Mφ while promoting Arg1+ Mφ via the E prostanoid 2 (EP2) receptor, accompanied by DNA methylation. Whole genome bisulfite sequencing revealed that PGE2-EP2 signaling drives hypermethylation and downregulation of gene sets related to myeloid cells in non-neoplastic tissues. Our study highlights PGE2-EP2-driven DNA methylation in the monocyte-to-TAM transition, suggesting potential therapeutic avenues for lung metastasis.