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 D PK that has documented anti-tumour activity associated with virus replication, PCD and cancer stem cell lysis. They are designed to examine whether D PK-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 D PK through virus replication and c-Jun N-terminal kinase/c-Jun activation. D PK-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, D PK also upregulated the secretion of inflammatory cytokines TNF-a, granulocyte macrophage colony-stimulating factor and IL-1b 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 D PK.

Follistatin‐like protein 1 contributes to dendritic cell and T‐lymphocyte activation in nasopharyngeal carcinoma patients by altering nuclear factor κb and Jun N‐terminal kinase expression

“…46 Simultaneously, ΔPK could activate JNK protein activity to suppress the expression of IL-10, which is an immunosuppressive factor. 47 On the basis of these results, we believe that FSTL1 plays a critical role in immune regulation by increasing the antigen presentation ability of DCs and T lymphocytes through altering NF-κb and JNK expression.…”

Oncolytic viruses as immunotherapy: progress and remaining challenges

“…MICA induction resulted from virus replication and JNK/c-Jun-dependent inhibition of secretion of the immunosuppressive cytokine IL-10 by melanoma cells. 51 Further studies are needed to better understand the relative contribution of different death pathways, including ICD, to the OV clinical efficacy.…”

“…However, OVs that naturally induce the secretion of multiple inflammatory cytokines (without genetic modification) ( Table 3 ) are desirable, particularly if they simultaneously inhibit tumor-promoting immunosuppressive functions, as we have recently shown for the HSV-2 OV, ΔPK. 51 Additional studies are needed in order to better understand these contributions, particularly within the context of different tumor types.…”

Targeting Nucleotide Biosynthesis: A Strategy for Improving the Oncolytic Potential of DNA Viruses

“…A HSV-2 mutant lacking part of the R1 N-terminal domain (ICP10ΔPK) replicated less efficiently in serum-starved cells and exhibited reduced virulence in animals, despite still being able to complex with R2 and catalyze dNTP synthesis ( 210 , 211 ). This virus is being tested as a candidate vaccine against genital herpes ( 212 ) but can also control the growth of human melanoma xenografts in nude mice ( 213 , 214 ). A similar version of this virus, called FusOn-H2, also exhibited growth restriction in serum-starved cells and controlled growth of xenografted human MDA-MB-435 melanomas ( 168 ) and EC9706 esophageal tumors ( 215 ) in nude mice.…”