title: Inhibition of STAT3 promotes the efficacy of adoptive transfer therapy using type-1 CTLs by modulation of the immunological microenvironment in a murine intracranial glioma.
abstract: A variety of cancers, including malignant gliomas, show aberrant activation of STAT3, which plays a pivotal role in negative regulation of antitumor immunity. We hypothesized that inhibition of STAT3 signals would improve the efficacy of T cell adoptive transfer therapy by reversal of STAT3-induced immunosuppression in a murine GL261 intracranial glioma model. In vitro treatment of GL261 cells with JSI-124, a STAT3 inhibitor, reversed highly phosphorylated status of STAT3. Systemic i.p. administration of JSI-124 in glioma-bearing immunocompetent mice, but not athymic mice, resulted in prolonged survival, suggesting a role of adaptive immunity in the antitumor effect. Furthermore, JSI-124 promoted maturation of tumor-infiltrating CD11c(+) dendritic cells and activation of tumor-conditioned cytotoxic T cells, enhanced dendritic cells and GL261 production of CXCL-10, a critical chemokine for attraction of Tc1 cells. When i.p. JSI-124 administration was combined with i.v. transfer of Pmel-I mouse-derived type-1 CTLs (Tc1), glioma-bearing mice exhibited prolonged survival compared with i.p. JSI-124 or i.v. Tc1 therapy alone. Flow cytometric analyses of brain infiltrating lymphocytes revealed that JSI-124-treatment enhanced the tumor-homing of i.v. transferred Tc1 cells in a CXCL-10-dependent fashion. Systemic JSI-124 administration also up-regulated serum IL-15 levels, and promoted the persistence of transferred Tc1 in the host. These data suggest that systemic inhibition of STAT3 signaling can reverse the suppressive immunological environment of intracranial tumor bearing mice both systemically and locally, thereby promoting the efficacy of adoptive transfer therapy with Tc1.
authors.affiliation: Department of Neurological Surgery and Brain Tumor Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhu
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sasaki
authors.forename: Ryo
authors.initials: R
authors.lastname: Ueda
authors.forename: Keri L
authors.initials: KL
authors.lastname: Low
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D005910:Glioma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D007276:Injections, Intraventricular; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D014315:Triterpenes / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D050796:STAT3 Transcription Factor; D014315:Triterpenes; C038106:cucurbitacin I