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

SUBMITTER: Bollino D

PROVIDER: S-EPMC5972308 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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ΔPK oncolytic activity includes modulation of the tumour cell milieu.

Bollino Dominique D Colunga Aric A Li Baiquan B Aurelian Laure L

The Journal of general virology 20151124 2

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- ...[more]

PMID: 26602205

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Project description:Aberrant production and/or function of multiple host systemic factors (e.g., metabolic and immune-inflammatory mediators) act in concert to promote a ‘tumorigenic’ host milieu that directly promotes an aggressive malignant phenotype as well as drug resistance. Hence, strategies with the capacity to simultaneously act across multiple host systemic pathways may be required to optimize therapeutic outcomes in solid tumors. We hypothesized that chronic aerobic training, a pleiotropic whole-body intervention, modulates multiple systemic host pathways that, in turn, effectively alters cancer cell phenotype in vitro. Plasma samples from patients with solid tumors exposed to chronic aerobic training or sedentary control were comprehensively characterized for changes in immune, inflammatory, and metabolic pathways. Compared with sedentary control, aerobic training caused significant reductions in interleukin (IL)-4, macrophage inflammatory protein-1 beta (MIP1-β), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), and hepatocyte growth factor (HGF). There were no significant changes in leukocyte phenotype or any plasma metabolite signatures. Exposure of estrogen receptor (ER) distinct human breast cancer cell lines (MCF-7 and MDA-MB-231) to post-intervention serum from breast cancer patients exposed to aerobic training caused marked increases in proliferation, migration, and apoptosis, compared to control patient serum. Only the combination of cytokines significantly reduced in plasma following aerobic training recapitulated the phenotype observed with patient serum in MCF-7 cells whereas only the single addition of MIP-1β or HGF significantly increased apoptosis in MDA-MB-231 cells. Co-culturing of MDA-MB-231 cells with patient exercise serum and a HGF neutralizing antibody increased proliferation and completely abrogated exercise serum-induced apoptosis. Finally, whole-genome microarray of MDA-MB-231 cells exposed to exercise or control patient serum revealed differential modulation of 310 genes including PTEN, CDK3, and IGFBP1. Our findings indicate the widespread potential of chronic aerobic training to modulate host immune-inflammatory systemic factors in patients with solid tumors. Modulation of such pathways directly alters breast cancer phenotypes providing novel insight into the molecular pathways by which exercise may inhibit malignant progression. MDA-MB-231 cells were plated at 250,000 cells/well in triplicate with 10% FBS in 6-well plates and left overnight to adhere. Media was suctioned off and replaced with serum free media. Patient serum was then added to the wells at a 10% final concentration and RNA was harvested using Qiagen RNeasy kit after 4 days.

Project description:Aberrant production and/or function of multiple host systemic factors (e.g., metabolic and immune-inflammatory mediators) act in concert to promote a âtumorigenicâ host milieu that directly promotes an aggressive malignant phenotype as well as drug resistance. Hence, strategies with the capacity to simultaneously act across multiple host systemic pathways may be required to optimize therapeutic outcomes in solid tumors. We hypothesized that chronic aerobic training, a pleiotropic whole-body intervention, modulates multiple systemic host pathways that, in turn, effectively alters cancer cell phenotype in vitro. Plasma samples from patients with solid tumors exposed to chronic aerobic training or sedentary control were comprehensively characterized for changes in immune, inflammatory, and metabolic pathways. Compared with sedentary control, aerobic training caused significant reductions in interleukin (IL)-4, macrophage inflammatory protein-1 beta (MIP1-Î²), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-Î±), and hepatocyte growth factor (HGF). There were no significant changes in leukocyte phenotype or any plasma metabolite signatures. Exposure of estrogen receptor (ER) distinct human breast cancer cell lines (MCF-7 and MDA-MB-231) to post-intervention serum from breast cancer patients exposed to aerobic training caused marked increases in proliferation, migration, and apoptosis, compared to control patient serum. Only the combination of cytokines significantly reduced in plasma following aerobic training recapitulated the phenotype observed with patient serum in MCF-7 cells whereas only the single addition of MIP-1Î² or HGF significantly increased apoptosis in MDA-MB-231 cells. Co-culturing of MDA-MB-231 cells with patient exercise serum and a HGF neutralizing antibody increased proliferation and completely abrogated exercise serum-induced apoptosis. Finally, whole-genome microarray of MDA-MB-231 cells exposed to exercise or control patient serum revealed differential modulation of 310 genes including PTEN, CDK3, and IGFBP1. Our findings indicate the widespread potential of chronic aerobic training to modulate host immune-inflammatory systemic factors in patients with solid tumors. Modulation of such pathways directly alters breast cancer phenotypes providing novel insight into the molecular pathways by which exercise may inhibit malignant progression. MDA-MB-231 cells were plated at 250,000 cells/well in triplicate with 10% FBS in 6-well plates and left overnight to adhere. Media was suctioned off and replaced with serum free media. Patient serum was then added to the wells at a 10% final concentration and RNA was harvested using Qiagen RNeasy kit after 4 days.

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?PK oncolytic activity includes modulation of the tumour cell milieu.

Publications

ΔPK oncolytic activity includes modulation of the tumour cell milieu.

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