Transcriptome analysis of pancreatic cancer cells with genetically modified Ptges or Ptger4

Tumor cell-derived prostaglandin E2 (PGE2) is a tumor cell-intrinsic factor that supports immunosuppression in the tumor microenvironment (TME) by acting on the immune cells, but the impact of PGE2 signaling in tumor cells is unclear. We demonstrate that deleting the PGE2 synthesis enzyme or disrupting autocrine PGE2 signaling through EP4 receptors on tumor cells reverses the T cell-low, myeloid cell-rich TME, activates T cells, and suppresses tumor growth. Mechanistically, Ptges and Ptger4 KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-a killing, and exhibited reduced adenosine synthesis. Our study reveals an unexpected finding – a non-redundant role for the autocrine mPGES1-PGE2-EP4 signaling axis in pancreatic cancer cells, further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing approaches in cancer therapy. This project aims to identify the immunosuppressive mechanisms of the Ptges-PGE2-Ptger4 axis in pancreatic cancer. We utilized non-T cell-inflamed pancreatic cancer cell lines and genetically modified Ptges or Ptger4 gene in these cell lines and compared gene expression profiles between control and Ptges-deficient or Ptger4-deficient cell lines in vitro and in vivo.