Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-α and IFN-γ dependent manners

X Zhu, BA Fallert-Junecko, M Fujita, R Ueda… - Cancer Immunology …, 2010 - Springer
X Zhu, BA Fallert-Junecko, M Fujita, R Ueda, G Kohanbash, ER Kastenhuber, HA McDonald…
Cancer Immunology, Immunotherapy, 2010Springer
Stimulation of double-stranded (ds) RNA receptors can increase the effectiveness of cancer
vaccines, but the underlying mechanisms are not completely elucidated. In this study, we
sought to determine critical roles of host IFN-α and IFN-γ pathways in the enhanced
therapeutic efficacy mediated by peptide vaccines and polyinosinic-polycytidylic acid [poly (I:
C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in the murine central
nervous system (CNS) GL261 glioma. C57BL/6-background wild type (WT), IFN-α receptor-1 …
Abstract
Stimulation of double-stranded (ds)RNA receptors can increase the effectiveness of cancer vaccines, but the underlying mechanisms are not completely elucidated. In this study, we sought to determine critical roles of host IFN-α and IFN-γ pathways in the enhanced therapeutic efficacy mediated by peptide vaccines and polyinosinic-polycytidylic acid [poly(I:C)] stabilized by lysine and carboxymethylcellulose (poly-ICLC) in the murine central nervous system (CNS) GL261 glioma. C57BL/6-background wild type (WT), IFN-α receptor-1 (IFN-αR1)−/− or IFN-γ −/− mice bearing syngeneic CNS GL261 glioma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes with or without intramuscular (i.m.) injections of poly-ICLC. The combinational treatment induced a robust transcription of CXCL10 in the glioma site. Blockade of CXCL10 with a specific monoclonal antibody (mAb) abrogated the efficient CNS homing of antigen-specific type-1 CTL (Tc1). Both IFN-αR −/− and IFN-γ −/− hosts failed to up-regulate the CXCL10 mRNA and recruit Tc1 cells to the tumor site, indicating non-redundant roles of type-1 and type-2 IFNs in the effects of poly-ICLC-assisted vaccines. The efficient trafficking of Tc1 also required Tc1-derived IFN-γ. Our data point to critical roles of the host-IFN-α and IFN-γ pathways in the modulation of CNS glioma microenvironment, and the therapeutic effectiveness of poly-ICLC-assisted glioma vaccines.
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