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.

Dietary Curcumin Attenuates Glioma Growth in a Syngeneic Mouse Model by Inhibition of the JAK1,2/STAT3 Signaling Pathway

“…On the other hand, knockdown of STAT3 in intracranial GL261 gliomas led to microglia and macrophage activation thus reversing immunosuppression and inhibiting tumor growth in vivo (51). In addition, systemic intraperitoneal administration of the STAT3 inhibitor JSI-124 resulted in long-term survival of GL261-bearing immunocompetent mice, but not of tumor-bearing athymic mice, suggesting a role of adaptive immunity in the observed antitumor effect (52). In intraperitoneally curcumin-treated immunocompromised mice (49), the survival time of treated animals was prolonged, yet did not prevent death.…”

Isocitrate dehydrogenase mutations suppress STAT1 and CD8+ T cell accumulation in gliomas

“…9,10). We have demonstrated that tumor-specific type 1 CD8 + T cells, which predominantly secrete IFN-γ, but not type 2 CD8 + T cells, can efficiently traffic into brain tumor sites and mediate effective tumor cell killing (11) via the type 1 chemokine CXCL10 (11)(12)(13)(14). Despite the importance of the type 1 T cell response, gliomas and other cancers secrete numerous type 2 cytokines (15-17) that promote tumor proliferation (18,19) and immune escape (20)(21)(22).…”

Alantolactone induces apoptosis in glioblastoma cells via GSH depletion, ROS generation, and mitochondrial dysfunction

“…At present, no ideal treatment exits for GBM and the median survival rate of patients with GBM remains less than 1 year after diagnosis. Despite recent advances in surgical resection, radiation therapy, and chemotherapy, the prognosis of glioblastoma continues to be dismal (3)(4)(5). Exploring novel therapeutic agents and their molecular mechanism are, therefore, necessary for improving the outcome of glioblastoma treatment.…”