title: Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells.
abstract: Improving effector T-cell functions is highly desirable for preventive or therapeutic interventions of diverse diseases. Signal transducer and activator of transcription 3 (Stat3) in the myeloid compartment constrains Th1-type immunity, dampening natural and induced antitumor immune responses. We have recently developed an in vivo small interfering RNA (siRNA) delivery platform by conjugating a Toll-like receptor 9 agonist with siRNA that efficiently targets myeloid and B cells. Here, we show that either CpG triggering combined with the genetic Stat3 ablation in myeloid/B cell compartments or administration of the CpG-Stat3siRNA drastically augments effector functions of adoptively transferred CD8+ T cells. Specifically, we show that both approaches are capable of increasing dendritic cell and CD8(+) T-cell engagement in tumor-draining lymph nodes. Furthermore, both approaches can significantly activate the transferred CD8(+) T cells in vivo, upregulating effector molecules such as perforin, granzyme B, and IFN-γ. Intravital multiphoton microscopy reveals that Stat3 silencing combined with CpG triggering greatly increases killing activity and tumor infiltration of transferred T cells. These results suggest the use of CpG-Stat3siRNA, and possibly other Stat3 inhibitors, as a potent adjuvant to improve T-cell therapies.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010-3000, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Herrmann
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Karen
authors.initials: K
authors.lastname: Reckamp
authors.forename: Brian
authors.initials: B
authors.lastname: Armstrong
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Claudia
authors.initials: C
authors.lastname: Kowolik
authors.forename: Jiehui
authors.initials: J
authors.lastname: Deng
authors.forename: Robert
authors.initials: R
authors.lastname: Figlin
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018899:CpG Islands / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000276:immunology*
chemical_list: D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse