Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity

Dmitriy Zamarin,Jacob Ricca,Taha Merghoub,Tamar Plitt,Padmanee Sharma,Rikke B Holmgaard,James P Allison,Peter Palese,Jedd D Wolchok

doi:10.1038/ncomms14340

Abstract

Emerging data suggest that locoregional cancer therapeutic approaches with oncolytic viruses can lead to systemic anti-tumour immunity, although the appropriate targets for intratumoral immunomodulation using this strategy are not known. Here we find that intratumoral therapy with Newcastle disease virus (NDV), in addition to the activation of innate immunity, upregulates the expression of T-cell co-stimulatory receptors, with the inducible co-stimulator (ICOS) being most notable. To explore ICOS as a direct target in the tumour, we engineered a recombinant NDV-expressing ICOS ligand (NDV-ICOSL). In the bilateral flank tumour models, intratumoral administration of NDV-ICOSL results in enhanced infiltration with activated T cells in both virus-injected and distant tumours, and leads to effective rejection of both tumours when used in combination with systemic CTLA-4 blockade. These findings highlight that intratumoral immunomodulation with an oncolytic virus expressing a rationally selected ligand can be an effective strategy to drive systemic efficacy of immune checkpoint blockade.

Highlights

Emerging data suggest that locoregional cancer therapeutic approaches with oncolytic viruses can lead to systemic anti-tumour immunity, the appropriate targets for intratumoral immunomodulation using this strategy are not known
We have explored this strategy using oncolytic Newcastle disease virus (NDV) and demonstrated that localized tumour infection with NDV-induced lymphocytic infiltration within virus-injected and distant tumours, resulting in regression of all tumours when combined with systemic CTLA-4 blockade[13]
Here we have identified the inducible co-stimulator (ICOS) as a pathway upregulated in NDV-infected tumours and investigated it as a target using recombinant NDV expressing the ICOS ligand (ICOSL) directly within the tumour microenvironment

Summary

Introduction

Emerging data suggest that locoregional cancer therapeutic approaches with oncolytic viruses can lead to systemic anti-tumour immunity, the appropriate targets for intratumoral immunomodulation using this strategy are not known. Oncolytic viruses (OVs) present an attractive strategy for locoregional immune activation, leading to immunogenic cell death, antigen release and production of type I interferon (IFN)—all factors required for efficient dendritic cell (DC) maturation and cross-presentation of tumour antigens[10,11,12] We have explored this strategy using oncolytic Newcastle disease virus (NDV) and demonstrated that localized tumour infection with NDV-induced lymphocytic infiltration within virus-injected and distant tumours, resulting in regression of all tumours when combined with systemic CTLA-4 blockade[13]. This effect is not limited to NDV and recent studies have demonstrated that other OVs could be used to potentiate the efficacy of immune checkpoint blockade[14,15,16]. With OV therapy, such targets are governed by complex interactions of a specific OV with the tumour microenvironment, and are influenced by individual virus biology, its replication and lytic potential, and its effects on the tumour cells and stromal cells

Methods

Results

Conclusion