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, Ling Jing, Yanbin Kuang, Tuo Zhang, Siwei Zhang, Feng Yao, Binhua P. Zhou, Jiong Deng
Abstract
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/PGE 2 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/PGE 2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE 2 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 PGE 2 signaling in Gprc5a -ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE 2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a -ko mouse model.