The immune system can act as an extrinsic suppressor of tumors. Therefore, tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here, we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells, and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells, T cells, natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3−/− hematopoietic cells, and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell– and NK cell–dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.
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We would like to thank G. Gao for statistical analyses, C. Muro-Cacho for evaluating immunohistochemical data, K. Nguyen and T. Ghansah for sharing their expertise and L. Lutz for technical assistance. This work was supported by US National Institutes of Health grants (to H.Y.), and by the Dr. Tsai-fan Yu Cancer Research Endowment. Work in D.P.'s lab was supported by grants from the Commonwealth Foundation, Janey Fund, the Seraph Foundation, the Topecers and D. Needle. W.G.K. is the Newman Scholar of the Leukemia and Lymphoma Society. We would also like to thank S. Akira and K. Takeda for Stat3loxP mice, and the Pathology Core at the University of South Florida for technical assistance. We also acknowledge dedication of staff members at the animal facilities and flow cytometry cores at both Moffitt Cancer Center and Johns Hopkins Cancer Center.
The authors declare no competing financial interests.
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Effects of Stat3 ablation on CD8+ and B220+ CD11c+ DCs. (PDF 208 kb)
IL-10 activates Stat3 in both NK cells and granulocytes. (PDF 182 kb)
FasL expression is increased in tumorinfiltrating neutrophils in Stat3−/− mice. (PDF 193 kb)
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No major toxic effects of long-term Stat3 inhibition by a small-molecule drug. (PDF 26 kb)
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Kortylewski, M., Kujawski, M., Wang, T. et al. Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat Med 11, 1314–1321 (2005) doi:10.1038/nm1325
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