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

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.