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Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma¹

Mitsugu Fujita^*,, Xinmei Zhu^*,, Kotaro Sasaki^*,, Ryo Ueda^*,, Keri L. Low^*,, Ian F. Pollack^*, and Hideho Okada^2,*,,

^* Department of Neurological Surgery, Department of Surgery, and Department of Dermatology and Immunology, University of Pittsburgh School of Medicine; and Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from National Institutes of Health/National Institute of Neurological Disorders and Stroke (P01 NS40923) (to H.O. and I.F.P.), from National Institutes of Health/National Cancer Institute (1P01 CA100327) (to H.O.), and a grant from the James S. McDonnell Foundation (to H.O.).

² Address correspondence and reprint requests to Dr. Hideho Okada, G12a Research Pavilion of the Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213. E-mail address: okadah{at}upmc.edu

³ Abbreviations used in this paper: GAA, glioma-associated Ag; Tc1, type 1 CTL; VEGF, vascular endothelial growth factor; rm, mouse recombinant; rh, human recombinant; CM, conditioned media; SPC, splenocyte; i.c., intracranial; BIL, brain infiltrating lymphocyte; poly-ICLC, polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose.