Cancer Immunology, Immunotherapy

, Volume 59, Issue 9, pp 1401–1409 | Cite as

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

  • Xinmei Zhu
  • Beth A. Fallert-Junecko
  • Mitsugu Fujita
  • Ryo Ueda
  • Gary Kohanbash
  • Edward R. Kastenhuber
  • Heather A. McDonald
  • Yan Liu
  • Pawel Kalinski
  • Todd A. Reinhart
  • Andres M. Salazar
  • Hideho Okada
Original Article

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.

Keywords

CNS glioma Poly-ICLC Glioma vaccine Type-1 immune response Chemokine 

Abbreviations

BIL

Brain infiltrating lymphocyte

CNS

Central nervous system

mAb

Monoclonal antibody

GAA

Glioma-associated antigen

Tc1

CTL with type-1 phenotype

Supplementary material

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Xinmei Zhu
    • 1
    • 2
  • Beth A. Fallert-Junecko
    • 3
  • Mitsugu Fujita
    • 1
    • 2
  • Ryo Ueda
    • 1
    • 2
  • Gary Kohanbash
    • 2
    • 3
  • Edward R. Kastenhuber
    • 2
  • Heather A. McDonald
    • 2
  • Yan Liu
    • 1
  • Pawel Kalinski
    • 4
  • Todd A. Reinhart
    • 3
  • Andres M. Salazar
    • 5
  • Hideho Okada
    • 1
    • 2
    • 4
    • 6
  1. 1.Department of Neurological SurgeryUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Brain Tumor ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  3. 3.Department of Infectious Diseases/Microbiology, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA
  4. 4.Department of Surgery and ImmunologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  5. 5.Oncovir Inc.Washington DCUSA
  6. 6.G12a Research Pavilion at Hillman Cancer CenterPittsburghUSA

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