Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity

Marcin Kortylewski, Maciej Kujawski, Tianhong Wang, Sheng Wei, Shumin Zhang, Shari Pilon-Thomas, Guilian Niu, Heidi Kay, James Mulé, William G. Kerr, Richard Jove, Drew Pardoll, Hua Yu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1314-1321
Number of pages8
JournalNature medicine
Volume11
Issue number12
DOIs
StatePublished - Dec 1 2005

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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