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

• Published in: Nature communications Vol. 8; no. 1; p. 14340
• Main Authors: Zamarin, Dmitriy, Holmgaard, Rikke B., Ricca, Jacob, Plitt, Tamar, Palese, Peter, Sharma, Padmanee, Merghoub, Taha, Wolchok, Jedd D., Allison, James P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.02.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/105; 13/106; 13/31; 42; 42/44; 59; 631/326/596/2561; 631/67/1059/2325; 64/60; Animals; Antigens; Cancer therapies; Cell Line, Tumor; CTLA-4 Antigen - immunology; CTLA-4 Antigen - metabolism; Humanities and Social Sciences; Humans; Immunomodulation - immunology; Inducible T-Cell Co-Stimulator Ligand - genetics; Inducible T-Cell Co-Stimulator Ligand - immunology; Inducible T-Cell Co-Stimulator Protein - genetics; Inducible T-Cell Co-Stimulator Protein - immunology; Inducible T-Cell Co-Stimulator Protein - metabolism; Ligands; Lymphocyte Activation - immunology; Lymphocytes; Melanoma; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neoplasms, Experimental - genetics; Neoplasms, Experimental - immunology; Neoplasms, Experimental - therapy; Newcastle disease virus - genetics; Newcastle disease virus - immunology; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Oncolytic Viruses - immunology; Recombination, Genetic; Science; Science (multidisciplinary); Toxicity; Tumors; Viruses; New York; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms14340

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. Oncolytic viruses induce a variety of immune targets in the infected tumours. Here, the authors show that Newcastle Disease Virus (NDV) upregulates the inducible co-stimulator (ICOS) on T cells and that intratumoral targeting of ICOS with engineered NDV in combination with CTLA-4 blockade induces systemic anti-tumour immunity in mice.