Poly-ICLC promotes the infiltration of effector T cells into intracranial gliomas via induction of CXCL10 in IFN-alpha and IFN-gamma dependent manners.
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.
Zhu
Xinmei
X
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Fallert-Junecko
Beth A
BA
Fujita
Mitsugu
M
Ueda
Ryo
R
Kohanbash
Gary
G
Kastenhuber
Edward R
ER
McDonald
Heather A
HA
Liu
Yan
Y
Kalinski
Pawel
P
Reinhart
Todd A
TA
Salazar
Andres M
AM
Okada
Hideho
H
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D019496:Cancer Vaccines; D002266:Carboxymethylcellulose Sodium / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016543:Central Nervous System Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry; D005910:Glioma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007114:Immunization; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry; D011070:Poly I-C / Q000008:administration & dosage*; D011107:Polylysine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D019138:Antibodies, Blocking; D019496:Cancer Vaccines; D054357:Chemokine CXCL10; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D053633:Receptor, Interferon alpha-beta; D011107:Polylysine; C019531:poly ICLC; D007371:Interferon-gamma; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C