TY - JOUR
T1 - Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-α and IFN-γ dependent manners
AU - Zhu, Xinmei
AU - Fallert-Junecko, Beth A.
AU - Fujita, Mitsugu
AU - Ueda, Ryo
AU - Kohanbash, Gary
AU - Kastenhuber, Edward R.
AU - McDonald, Heather A.
AU - Liu, Yan
AU - Kalinski, Pawel
AU - Reinhart, Todd A.
AU - Salazar, Andres M.
AU - Okada, Hideho
N1 - Funding Information:
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).
PY - 2010/9
Y1 - 2010/9
N2 - 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.
AB - 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.
KW - CNS glioma
KW - Chemokine
KW - Glioma vaccine
KW - Poly-ICLC
KW - Type-1 immune response
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UR - http://www.scopus.com/inward/citedby.url?scp=77955515616&partnerID=8YFLogxK
U2 - 10.1007/s00262-010-0876-3
DO - 10.1007/s00262-010-0876-3
M3 - Article
C2 - 20549206
AN - SCOPUS:77955515616
SN - 0340-7004
VL - 59
SP - 1401
EP - 1409
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
IS - 9
ER -
