Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity

Mubeen M Mosaheb,Jana Cable,Matthias Gromeier,Elena Y Dobrikova,Michael C Brown,Yuanfan Yang,David M Ashley,Darell D Bigner,Smita K Nair,Hideho Okada

doi:10.1038/s41467-019-13939-z

Mubeen M Mosaheb, Jana Cable + Show 8 more

Open Access

https://doi.org/10.1038/s41467-019-13939-z

Copy DOI

Abstract

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. Here we devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models.

Highlights

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens
We report the engineering of genetically stable vectors based on the highly attenuated PVSRIPO [type 1 poliovirus (Sabin) live-attenuated vaccine containing a rhinovirus type 2 internal ribosomal entry site (IRES)]8
We show that PVSRIPO-based vectors target DCs to: elicit sublethal viral translation and propagation resulting in expression of foreign epitopes in a highly adjuvated context; induce DC maturation markers; provoke type I/III interferon (IFN) release; present the H3.3K27M epitope to T cells; generate locoregional proinflammatory activation, immune cell infiltration and DC activation in vivo; and trigger DC migration to immunization site-draining lymph nodes in vivo, where they express the H3.3K27M epitope

Summary

Introduction

Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; they recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models. We show that PVSRIPO-based vectors target DCs to: elicit sublethal viral translation and propagation resulting in expression of foreign epitopes in a highly adjuvated context; induce DC maturation markers; provoke type I/III interferon (IFN) release; present the H3.3K27M epitope to T cells; generate locoregional proinflammatory activation, immune cell infiltration and DC activation in vivo; and trigger DC migration to immunization site-draining lymph nodes in vivo, where they express the H3.3K27M epitope. Vector immunization induces CD8 T cell infiltration into tumors, and exhibits significant anti-tumor efficacy in immunocompetent rodent tumor models

Methods

Results

Conclusion