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Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites.

Jennings VA, Ilett EJ, Scott KJ, West EJ, Vile R, Pandha H, Harrington K, Young A, Hall GD, Coffey M, Selby P, Errington-Mais F, Melcher AA - Int. J. Cancer (2013)

Bottom Line: A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells.Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing.Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL-12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response.

View Article: PubMed Central - PubMed

Affiliation: Targeted & Biological Therapies Group, Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.

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LAKDC and reovirus phenotypically mature iDC and produce proinflammatory cytokines in the presence of ascites. (a) Reovirus-loaded iDC or LAKDC were cultured in the absence (red line) or presence of 2.5% AF5 (green line) or AF14 (blue line) for 48 hr. DC (CD11c+ cells) were analyzed by flow cytometry for expression of maturation/activation markers, CD80 and CD86. Histogram plots are representative of two healthy donors. Shaded gray = isotype control, black line = unloaded DC controls [either iDC (left panel) or DC within LAKDC coculture (right panel)]. (b) Reovirus-loaded iDC and LAKDC were cultured for 48 hr ± ascites (AF5 and 14) before supernatants were collected and concentrations of IFNα were determined by ELISA. Graphs show the mean + SEM of four healthy donors.
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fig05: LAKDC and reovirus phenotypically mature iDC and produce proinflammatory cytokines in the presence of ascites. (a) Reovirus-loaded iDC or LAKDC were cultured in the absence (red line) or presence of 2.5% AF5 (green line) or AF14 (blue line) for 48 hr. DC (CD11c+ cells) were analyzed by flow cytometry for expression of maturation/activation markers, CD80 and CD86. Histogram plots are representative of two healthy donors. Shaded gray = isotype control, black line = unloaded DC controls [either iDC (left panel) or DC within LAKDC coculture (right panel)]. (b) Reovirus-loaded iDC and LAKDC were cultured for 48 hr ± ascites (AF5 and 14) before supernatants were collected and concentrations of IFNα were determined by ELISA. Graphs show the mean + SEM of four healthy donors.

Mentions: Previous studies have demonstrated the ability of both LAK cells and reovirus to mature iDC, an essential step for generation of antigen-specific adaptive T cell antitumor immunity.25,28 However, whether this applies in the context of malignant ascites, which may contain immunosuppressive factors that might impede DC maturation, has not been addressed. The ability of LAK cells and reovirus to phenotypically mature iDC in the presence of ascites was investigated by flow cytometry. Unloaded LAK cells induced cell surface expression of the activation/maturation markers, CD86 and CD80, on iDC to the same extent in both the absence and presence of ascitic fluid (Supporting Information Fig. S1). CD86 was further increased in reovirus-loaded LAKDC cocultures and, again, this was not impeded by the presence of ascitic fluid (Fig. 5a), suggesting that both LAK and reovirus can overcome potentially suppressive factors in the ascites.


Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites.

Jennings VA, Ilett EJ, Scott KJ, West EJ, Vile R, Pandha H, Harrington K, Young A, Hall GD, Coffey M, Selby P, Errington-Mais F, Melcher AA - Int. J. Cancer (2013)

LAKDC and reovirus phenotypically mature iDC and produce proinflammatory cytokines in the presence of ascites. (a) Reovirus-loaded iDC or LAKDC were cultured in the absence (red line) or presence of 2.5% AF5 (green line) or AF14 (blue line) for 48 hr. DC (CD11c+ cells) were analyzed by flow cytometry for expression of maturation/activation markers, CD80 and CD86. Histogram plots are representative of two healthy donors. Shaded gray = isotype control, black line = unloaded DC controls [either iDC (left panel) or DC within LAKDC coculture (right panel)]. (b) Reovirus-loaded iDC and LAKDC were cultured for 48 hr ± ascites (AF5 and 14) before supernatants were collected and concentrations of IFNα were determined by ELISA. Graphs show the mean + SEM of four healthy donors.
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Related In: Results  -  Collection

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fig05: LAKDC and reovirus phenotypically mature iDC and produce proinflammatory cytokines in the presence of ascites. (a) Reovirus-loaded iDC or LAKDC were cultured in the absence (red line) or presence of 2.5% AF5 (green line) or AF14 (blue line) for 48 hr. DC (CD11c+ cells) were analyzed by flow cytometry for expression of maturation/activation markers, CD80 and CD86. Histogram plots are representative of two healthy donors. Shaded gray = isotype control, black line = unloaded DC controls [either iDC (left panel) or DC within LAKDC coculture (right panel)]. (b) Reovirus-loaded iDC and LAKDC were cultured for 48 hr ± ascites (AF5 and 14) before supernatants were collected and concentrations of IFNα were determined by ELISA. Graphs show the mean + SEM of four healthy donors.
Mentions: Previous studies have demonstrated the ability of both LAK cells and reovirus to mature iDC, an essential step for generation of antigen-specific adaptive T cell antitumor immunity.25,28 However, whether this applies in the context of malignant ascites, which may contain immunosuppressive factors that might impede DC maturation, has not been addressed. The ability of LAK cells and reovirus to phenotypically mature iDC in the presence of ascites was investigated by flow cytometry. Unloaded LAK cells induced cell surface expression of the activation/maturation markers, CD86 and CD80, on iDC to the same extent in both the absence and presence of ascitic fluid (Supporting Information Fig. S1). CD86 was further increased in reovirus-loaded LAKDC cocultures and, again, this was not impeded by the presence of ascitic fluid (Fig. 5a), suggesting that both LAK and reovirus can overcome potentially suppressive factors in the ascites.

Bottom Line: A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells.Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing.Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNɣ, IL-12, IFNα and TNFα) and (iii) generate an innate and specific antitumor adaptive immune response.

View Article: PubMed Central - PubMed

Affiliation: Targeted & Biological Therapies Group, Leeds Institute of Molecular Medicine, University of Leeds, United Kingdom.

Show MeSH
Related in: MedlinePlus