Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity

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.

STAT3 in immune responses and inflammatory bowel diseases

“…We have demonstrated that loss of STAT3 in DCs blocked Flt3, but not GM-CSF signaling for DC differentiation, which consequently significantly affects T cell differentiation and activation (unpublished results). In consistency with this idea, a recent report revealed that STAT3 in DCs is involved in production of T regs during tumorigenesis [84].…”

Signal Transducer and Activator of Transcription 3 (Stat3C) Promotes Myeloid-Derived Suppressor Cell Expansion and Immune Suppression during Lung Tumorigenesis

“…*P Ͻ 0.05; **P Ͻ 0.01. topoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. 30 We previously identified inflammatory cell infiltration in tumor areas of CCSP-rtTA/(tetO) 7 -CMV-Stat3C bitransgenic mice. 1 How these cells contribute to tumor formation is not known.…”

Dynamic Balance of pSTAT1 and pSTAT3 in C57BL/6 Mice Infected with Lethal Or Nonlethal Plasmodium yoelii

“…pSTAT3, which has antagonistic effect on pSTAT1 (27,28), plays a key role in suppressing the function of neutrophils, NK cells, DCs (31)(32)(33) and negatively regulating the Th1-mediated inflammatory response (30,31). Therefore, the balance of pSTAT1 and pSTAT3 plays an important role in regulating immune response and maintaining immunohomeostasis.…”

“…pSTAT3, which has antagonistic effect on pSTAT1 (27,28), is not only a potent negative regulator of the Th1-mediated inflammatory response, but also an activator of many genes that are crucial for immune regulation (29,30). Down-regulation of STAT3 could enhance Th1 type immune response and activate DCs, NK cells and macrophages (31)(32)(33). So the balance of pSTAT1 and pSTAT3, which has been studied in cancer immunity (31,34), has an important role in regulation of immune responses.…”