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-alpha and IFN-beta, which are secreted by Stat3-inhibited
tumor cells, are able to activate macrophage NO production, whereas neutralizing
TNF-alpha 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.