title: ΔPK oncolytic activity includes modulation of the tumour cell milieu.
abstract: Oncolytic virotherapy is a unique cancer therapeutic that encompasses tumour cell lysis through both virus replication and programmed cell death (PCD) pathways. Nonetheless, clinical efficacy is relatively modest, likely related to the immunosuppressive tumour milieu. Our studies use the herpes simplex virus type 2 (HSV-2)-based oncolytic virus ΔPK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether ΔPK-mediated oncolysis includes the ability to reverse the immunosuppressive tumour microenvironment by altering the balance of cytokines directly secreted by the melanoma cells and to define its mechanism. Here, we show that melanoma cells secreted the immunosuppressive cytokine IL-10, and that secretion was inhibited by ΔPK through virus replication and c-Jun N-terminal kinase/c-Jun activation. ΔPK-induced IL-10 inhibition upregulated surface expression of MHC class I chain-related protein A, the ligand for the activating NKG2D receptor expressed on NK- and cytotoxic T-cells. Concomitantly, ΔPK also upregulated the secretion of inflammatory cytokines TNF-α, granulocyte macrophage colony-stimulating factor and IL-1β through autophagy-mediated activation of Toll-like receptor 2 pathways and pyroptosis, and it inhibited the expression of the negative immune checkpoint regulator cytotoxic T-lymphocyte antigen 4. Pharmacologic inhibition of these processes significantly reduces the oncolytic activity of ΔPK.
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bollino
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Aric
authors.initials: A
authors.lastname: Colunga
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Baiquan
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Laure
authors.initials: L
authors.lastname: Aurelian
mesh_terms: D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D002460:Cell Line; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000254:growth & development*; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008807:Mice, Inbred BALB C; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000254:growth & development*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C508609:IL10 protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048031:JNK Mitogen-Activated Protein Kinases