PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model

Tong Wang, Bo Jing, Dongliang Xu, Yueling Liao, Hongyong Song, Beibei Sun, Wenzheng Guo, Jianhua Xu, Kaimi Li, Min Hu, Shuli Liu, Jing Ling, Yanbin Kuang, Tuo Zhang, Siwei Zhang, Feng Yao, Binhua P. Zhou, Jiong Deng

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.

Original languageEnglish
Pages (from-to)3179-3194
Number of pages16
JournalOncogene
Volume39
Issue number15
DOIs
StatePublished - Apr 9 2020

Bibliographical note

Funding Information:
Acknowledgements This study was supported by grants from National Natural Science Foundation of China (81620108022, 91129303, 91729302 and 81572759 to JD, 81572693 to FY) and Shenzhen Municipal Government of China (KQTD20170810160226082).

Publisher Copyright:
© 2020, The Author(s).

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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