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

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-alpha and IFN-gamma 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-alpha receptor-1 (IFN-alphaR1)(-/-) or IFN-gamma(-/-) 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-alphaR(-/-) and IFN-gamma(-/-) 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-gamma. Our data point to critical roles of the host-IFN-alpha and IFN-gamma pathways in the modulation of CNS glioma microenvironment, and the therapeutic effectiveness of poly-ICLC-assisted glioma vaccines.

• Authors: 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
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 59 Issue 9 Pg. 1401-9 (Sep 2010) ISSN: 1432-0851 [Electronic] Germany
• PMID: 20549206 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Blocking
• Cancer Vaccines
• Chemokine CXCL10
• Epitopes, T-Lymphocyte
• Peptide Fragments
• Receptor, Interferon alpha-beta
• Polylysine
• poly ICLC
• Interferon-gamma
• Carboxymethylcellulose Sodium
• Poly I-C

Topics

• Animals
• Antibodies, Blocking (administration & dosage)
• Cancer Vaccines
• Carboxymethylcellulose Sodium (administration & dosage, analogs & derivatives)
• Cell Line, Tumor
• Cell Movement (drug effects, genetics, immunology)
• Central Nervous System Neoplasms (immunology, pathology, therapy)
• Chemokine CXCL10 (biosynthesis, genetics, immunology)
• Epitopes, T-Lymphocyte (chemistry)
• Glioma (immunology, pathology, therapy)
• Immunization
• Interferon-gamma (genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasm Transplantation
• Peptide Fragments (administration & dosage, chemistry)
• Poly I-C (administration & dosage)
• Polylysine (administration & dosage, analogs & derivatives)
• Receptor, Interferon alpha-beta (genetics)
• T-Lymphocytes, Cytotoxic (drug effects, immunology, metabolism, pathology)