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July 2017

J Exp Med. 2017 Jul 24. pii: jem.20160392. doi: 10.1084/jem.20160392. [Epub ahead of print]

S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis viaNLRP3/IL-1β.

Weichand B, Popp R, Dziumbla S, Mora J, Strack E, Elwakeel E, Frank AC, Scholich K, Pierre S, Syed SN, Olesch C, Ringleb J, Ören B, Döring C, Savai R, Jung M, von Knethen A, Levkau B, Fleming I, Weigert A, Brüne B.

Tumor-associated inflammation contributes to all stages of tumor development. Among the tumor-infiltrating immune cells that propagate cancer, macrophages constitute a major population. Their density correlates with poor prognosis in a variety of solid tumors, including breast cancer, gastric cancer, lung cancer, and lymphoma. Mechanisms of tumorigenic TAM activity in the primary tumor range from promoting tumor cell survival, therapeutic resistance and suppressing antitumor immunity, to fostering angiogenesis and invasiveness, which promotes metastatic spread. Because metastatic disease is the primary cause of patient death, there is an urgent need to understand molecular mechanisms by which the tumor microenvironment, including TAMs, promotes metastasis. Such an understanding may open potential therapeutic strategies to prevent or treat metastatic disease. In this work, the authors identified that genetic deletion of the S1P receptor 1 (S1pr1) alone in TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Transcriptome analysis of isolated TAMs from both entities revealed reduced expression of the inflammasome component Nlrp3 in S1PR1-deficient TAMs. Macrophage-dependent lymphangiogenesis in vitro was triggered upon inflammasome activation and required both S1PR1 signaling and IL-1β production. Finally, NLRP3 expression in tumor infiltrating macrophages correlated with survival, lymph node invasion, and metastasis of mammary carcinoma patients. Conceptually, the study indicates an unappreciated role of the NLRP3 inflammasome in promoting metastasis via the lymphatics downstream of S1PR1 signaling in macrophages.