Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models

Xinmei Zhu,Junichi Eguchi,Walter J Storkus,Andres M Salazar,Mitsugu Fujita,Paul R Walker,Hideho Okada,Fumihiko Nishimura,Wendy Fellows-Mayle,Jill E Dusak,Kotaro Sasaki

doi:10.1186/1479-5876-5-10

Abstract

BackgroundToll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). To improve the efficacy of vaccine strategies directed against CNS tumors, we evaluated whether administration of a TLR3 ligand, polyinosinic-polycytidylic (poly-IC) stabilized with poly-lysine and carboxymethylcellulose (poly-ICLC) would enhance the anti-CNS tumor effectiveness of tumor peptide-based vaccinations.MethodsC57BL/6 mice bearing syngeneic CNS GL261 glioma or M05 melanoma received subcutaneous (s.c.) vaccinations with synthetic peptides encoding CTL epitopes- mEphA2 (671–679), hgp100 (25–33) and mTRP-2 (180–188) for GL261, or ovalbumin (OVA: 257–264) for M05. The mice also received intramuscular (i.m.) injections with poly-ICLC.ResultsThe combination of subcutaneous (s.c.) peptide-based vaccination and i.m. poly-ICLC administration promoted systemic induction of antigen (Ag)-specific Type-1 CTLs expressing very late activation antigen (VLA)-4, which confers efficient CNS-tumor homing of vaccine-induced CTLs based on experiments with monoclonal antibody (mAb)-mediated blockade of VLA-4. In addition, the combination treatment allowed expression of IFN-γ by CNS tumor-infiltrating CTLs, and improved the survival of tumor bearing mice in the absence of detectable autoimmunity.ConclusionThese data suggest that poly-ICLC, which has been previously evaluated in clinical trials, can be effectively combined with tumor Ag-specific vaccine strategies, thereby providing a greater index of therapeutic efficacy.

Highlights

Toll-like receptor (TLR)3 ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS)
Even though efficient tumor-homing by Ag-specific CD8+ T cells most likely results from the orchestrated cooperation of multiple receptor-ligand combinations [29], these results indicate that poly-ICLC induced very late activation antigen (VLA)-4 expression on vaccineinduced CTL dominantly influences their capacity to infiltrate into CNS tumors
Luxol Fast Blue (LFB) and Hematoxylin and Eosin (H&E) staining suggest the lack of autoimmune encephalitis in mice treated with glioma-associated antigens (GAAs)-vaccines and poly-ICLC To determine whether the combination therapy with GAA-vaccines and poly-ICLC administration induces demyelination and/or autoimmune encephalitis, we evaluated brain sections obtained from treated mice by LFB staining and H&E staining using standard protocols [30]

Summary

Introduction

Toll-like receptor (TLR) ligands serve as natural inducers of pro-inflammatory cytokines capable of promoting Type-1 adaptive immunity, and TLR3 is abundantly expressed by cells within the central nervous system (CNS). Our long-term goal is to develop safe and effective immunotherapeutic modalities for CNS tumors, such as gliomas To this end, we have been directing our major focus on factors that promote the efficacy of peripheral vaccinations against CNS tumor-associated or specific Ags. our recent study using adoptive transfer of ex vivo activated T-cells has demonstrated that a Type-1 phenotype for tumor-Ag specific CTLs is critical for efficient CNS tumor-tropism and for the resulting anti-tumor therapeutic efficacy, which can be further facilitated by genetic delivery of IFN-α into CNS tumor sites [1]. Given that IFN-α up-regulates VLA-4 on human T-cells [20], we hypothesized that poly-ICLC might enhance VLA-4 expression on vaccineinduced Ag-specific CTLs, thereby facilitating the CNStumor homing of these CTLs. We show that polyICLC administration enhances the therapeutic efficacy of the Ag-specific vaccines, in part, by promoting the induction of Type-1 Ag-specific VLA-4+ CTLs in the i.c. M05 melanoma and GL261 glioma models

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Conclusion