ΔPK oncolytic activity includes modulation of the tumour cell milieu
| Autor: | Baiquan Li, Aric Colunga, Laure Aurelian, Dominique Bollino |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Herpesvirus 2 Human medicine.medical_treatment Apoptosis Biology medicine.disease_cause Cell Line 03 medical and health sciences Cancer stem cell Virology Autophagy Immune Tolerance medicine Animals Humans Cytotoxic T cell Melanoma Oncolytic Virotherapy Mice Inbred BALB C Tumor Necrosis Factor-alpha JNK Mitogen-Activated Protein Kinases Pyroptosis Granulocyte-Macrophage Colony-Stimulating Factor Toll-Like Receptor 2 Standard Immune checkpoint Interleukin-10 Oncolytic virus Oncolytic Viruses Treatment Outcome 030104 developmental biology Cytokine Herpes simplex virus Cancer research |
| Zdroj: | Journal of General Virology. 97:496-508 |
| ISSN: | 1465-2099 0022-1317 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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