title: Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity.
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.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Weill Cornell Medical College, New York, New York 10065, USA.|Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Zamarin
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Rikke B
authors.initials: RB
authors.lastname: Holmgaard
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ricca
authors.affiliation: Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Plitt
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Palese
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Padmanee
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Weill Cornell Medical College, New York, New York 10065, USA.|Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Taha
authors.identifier: 0000-0002-1518-5111
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Weill Cornell Medical College, New York, New York 10065, USA.|Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D056747:Immunomodulation / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D009522:Newcastle disease virus / Q000235:genetics / Q000276:immunology*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology*; D011995:Recombination, Genetic
chemical_list: D060908:CTLA-4 Antigen; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein