Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity.
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.
Kortylewski
Marcin
M
H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, Florida 33612, USA.
Kujawski
Maciej
M
Wang
Tianhong
T
Wei
Sheng
S
Zhang
Shumin
S
Pilon-Thomas
Shari
S
Niu
Guilian
G
Kay
Heidi
H
Mulé
James
J
Kerr
William G
WG
Jove
Richard
R
Pardoll
Drew
D
Yu
Hua
H
D000704:Analysis of Variance; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D045744:Cell Line, Tumor; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D020868:Gene Silencing; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse