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

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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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Abbreviations

BIL:

Brain infiltrating lymphocyte

CNS:

Central nervous system

mAb:

Monoclonal antibody

GAA:

Glioma-associated antigen

Tc1:

CTL with type-1 phenotype

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Acknowledgments

We appreciate generous funding from Musella Foundation, Pittsburgh Foundation as well as the following funds from the National Institute of Health (NIH): 1R01NS055140 (Hideho Okada), 1P01CA100327 (Hideho Okada), 2P01NS40923 (Hideho Okada) and 1P01 CA132714 (Pawel Kalinski, Todd A. Reinhart and Hideho Okada).

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Authors and Affiliations

  1. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Xinmei Zhu, Mitsugu Fujita, Ryo Ueda, Yan Liu & Hideho Okada

  2. Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Xinmei Zhu, Mitsugu Fujita, Ryo Ueda, Gary Kohanbash, Edward R. Kastenhuber, Heather A. McDonald & Hideho Okada

  3. Department of Infectious Diseases/Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Beth A. Fallert-Junecko, Gary Kohanbash & Todd A. Reinhart

  4. Department of Surgery and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Pawel Kalinski & Hideho Okada

  5. Oncovir Inc., Washington DC, USA

    Andres M. Salazar

  6. G12a Research Pavilion at Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA

    Hideho Okada

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  1. Xinmei Zhu
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  2. Beth A. Fallert-Junecko
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  3. Mitsugu Fujita
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  12. Hideho Okada
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Correspondence to Hideho Okada.

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Zhu, X., Fallert-Junecko, B.A., Fujita, M. et al. Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-α and IFN-γ dependent manners. Cancer Immunol Immunother 59, 1401–1409 (2010). https://doi.org/10.1007/s00262-010-0876-3

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  • DOI: https://doi.org/10.1007/s00262-010-0876-3

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