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Stat3 Activity in Melanoma Cells Affects Migration of Immune Effector Cells and Nitric Oxide-Mediated Antitumor Effects¹

Lyudmila Burdelya^2,3,*, Maciej Kujawski^2,*, Guilian Niu^*, Bin Zhong^*, Tianhong Wang, Shumin Zhang^*, Marcin Kortylewski^*, Kenneth Shain^*, Heidi Kay, Julie Djeu^*, William Dalton^*, Drew Pardoll, Sheng Wei^* and Hua Yu^4,*

^* H. Lee Moffitt Cancer Center and Research Institute and Department of Oncology, College of Medicine, University of South Florida, Tampa, FL 33612; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and College of Public Health, University of South Florida, Tampa, FL 33612

Infiltration of immune effector cells in tumors is critical for antitumor immune responses. However, what regulates immune cell infiltration of tumors remains to be identified. Stat3 is constitutively activated with high frequency in diverse cancers, promoting tumor cell growth and survival. Blocking Stat3 signaling in tumors in vivo results in tumor growth inhibition that involves killing of nontransfected tumor cells and infiltration of immune effector cells, suggesting that Stat3 activity in tumor cells might affect immune cell recruitment. However, dying tumor cells can also attract immune cells. In this study, we show in isogenic murine melanomas that natural Stat3 activity is associated with tumor growth and reduction of T cell infiltration. Blocking Stat3 signaling in the melanoma cells containing high Stat3 activity results in expression of multiple chemoattractants, leading to increased migration of lymphocytes, NK cells, neutrophils, and macrophages. In addition, blocking Stat3 triggers tumor cells to produce soluble factors capable of activating macrophage production of NO in vitro and in vivo. TNF- and IFN-, which are secreted by Stat3-inhibited tumor cells, are able to activate macrophage NO production, whereas neutralizing TNF- in the tumor supernatant from Stat3-blocked tumor cells abrogates nitrite production. Moreover, interrupting Stat3 signaling in tumor cells leads to macrophage-mediated, nitrite-dependent cytostatic activity against nontransduced tumor cells. These results suggest that tumor Stat3 activity affects recruitment of diverse immune effectors and it can be manipulated to activate the effector phase of innate immune responses.

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