Pivotal roles for cancer cell–intrinsic mPGES-1 and autocrine EP4 signaling in suppressing antitumor immunity

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 on the immunosuppressive TME 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. Knockout (KO) of Ptges (the gene encoding the PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D P53R172H Yfp CrePdx) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner. Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges- and Ptger4-KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α-induced killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4-KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected finding - a nonredundant role for the autocrine mPGES-1/PGE2/EP4 signaling axis in pancreatic cancer cells, further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing therapy in cancer.

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Publication Details

Journal
JCI Insight
Published
2024-09-19
DOI
https://doi.org/10.1172/jci.insight.178644
Citations
8
Primary Topic
Inflammatory mediators and NSAID effects
Type
article
Field-Weighted Citation Impact
3.58

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article

Pivotal roles for cancer cell–intrinsic mPGES-1 and autocrine EP4 signaling in suppressing antitumor immunity

Noah Cheng, John W. Tobias, Charu Arora, Nikhil Joshi et al.
8 citations
JCI Insight
Inflammatory mediators and NSAID effects
3.58
article

Pivotal roles for cancer cell–intrinsic mPGES-1 and autocrine EP4 signaling in suppressing antitumor immunity

Noah Cheng, John W. Tobias, Charu Arora, Nikhil Joshi, Varenka Rodriguez DiBlasi, Garret A. FitzGerald, Robert H. Vonderheide, Ben Z. Stanger, Emily Corse, Li-Chuan Chan, Nune Markosyan, Il‐Kyu Kim, Emer M. Smyth, Emma Y Schechter, Kang Liu, Liz Quinones-Ware, Joseph E Hochberg
article en
8 citations

Abstract

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 on the immunosuppressive TME 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. Knockout (KO) of Ptges (the gene encoding the PGE2 synthesis enzyme mPGES-1) or the EP4 receptor gene (Ptger4) in KPCY (KrasG12D P53R172H Yfp CrePdx) pancreatic tumor cells abolished growth of implanted tumors in a T cell-dependent manner. Blockade of the EP4 receptor in combination with immunotherapy, but not immunotherapy alone, induced complete tumor regressions and immunological memory. Mechanistically, Ptges- and Ptger4-KO tumor cells exhibited altered T and myeloid cell attractant chemokines, became more susceptible to TNF-α-induced killing, and exhibited reduced adenosine synthesis. In hosts treated with an adenosine deaminase inhibitor, Ptger4-KO tumor cells accumulated adenosine and gave rise to tumors. These studies reveal an unexpected finding - a nonredundant role for the autocrine mPGES-1/PGE2/EP4 signaling axis in pancreatic cancer cells, further nominating mPGES-1 inhibition and EP4 blockade as immune-sensitizing therapy in cancer.

JCI InsightVol. 9(21)
Columbia University Irving Medical Center (US), Parker Institute for Cancer Immunotherapy (US), Cancer Research Institute of the Slovak Academy of Sciences (SK), Translational Therapeutics (United States) (US), Penn Center for AIDS Research (US), Boehringer Ingelheim (United States) (US), Abramson Cancer Center (US), University of Pennsylvania (US)
American Cancer Society, American Heart Association, Breast Cancer Research Foundation, University of Pennsylvania, Parker Institute for Cancer Immunotherapy, Volkswagen Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences
Good health and well-being
Openalex Percentile: Top 7%
Inflammatory mediators and NSAID effects
3.58
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