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

Oncogene 2020 Apr

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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.

Citation

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. PTGES/PGE2 signaling links immunosuppression and lung metastasis in Gprc5a-knockout mouse model. Oncogene. 2020 Apr;39(15):3179-3194