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Systemic CD8+ T cell-mediated tumoricidal effects by intratumoral treatment of oncolytic herpes simplex virus with the agonistic monoclonal antibody for murine glucocorticoid-induced tumor necrosis factor receptor.

Ishihara M, Seo N, Mitsui J, Muraoka D, Tanaka M, Mineno J, Ikeda H, Shiku H - PLoS ONE (2014)

Bottom Line: In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor.The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry.Studies using Fc-digested DTA-1 and Fcγ receptor knockout mice demonstrated the direct participation of DTA-1 in regulatory T cell depletion by antibody-dependent cellular cytotoxicity primarily via macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.

ABSTRACT
Oncolytic virotherapy combined with immunomodulators is a novel noninvasive strategy for cancer treatment. In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor. Two murine tumor models were used to evaluate the therapeutic efficacies of HF10 virotherapy combined with DTA-1. The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry. Intratumoral administration of HF10 in combination with DTA-1 at a low dose resulted in a more vigorous attenuation of growth of the untreated contralateral as well as the treated tumors than treatment with either HF10 or DTA-1 alone. An accumulation of CD8(+) T cells, including tumor- and herpes simplex virus type-1-specific populations, and a decrease in the number of CD4(+) Foxp3(+) T regulatory cells were seen in both HF10- and DTA-1-treated tumors. Studies using Fc-digested DTA-1 and Fcγ receptor knockout mice demonstrated the direct participation of DTA-1 in regulatory T cell depletion by antibody-dependent cellular cytotoxicity primarily via macrophages. These results indicated the potential therapeutic efficacy of a glucocorticoid-induced tumor necrosis factor receptor-specific monoclonal antibody in oncolytic virotherapy at local tumor sites.

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Tumor growth following intratumoral administration of HF10 with/without DTA-1.Growth (mm2) of subcutaneously inoculated CT26/NY-ESO-1 (A) or CMS5a cells (B) following i.t. treatment with HF10 (open triangles) and/or DTA-1 (closed triangles) on indicated days. Purified rat IgG was used as a control for DTA-1. Data shown in Fig. 1 1 are representative of four independent experiments. By the Kruskal-Wallis ANOVA test, the CT26/NY-ESO-1 growth inhibition by combined treatment with HF10 and DTA-1 was significantly different from the HF10-treated or untreated control at day 42. CMS5a growth inhibition by the HF10 and DTA-1 combination was significantly different from the DTA-1-treated or untreated control at day 25. CMS5a growth inhibition was also significantly different in the HF10-treated group compared with the untreated control.
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pone-0104669-g001: Tumor growth following intratumoral administration of HF10 with/without DTA-1.Growth (mm2) of subcutaneously inoculated CT26/NY-ESO-1 (A) or CMS5a cells (B) following i.t. treatment with HF10 (open triangles) and/or DTA-1 (closed triangles) on indicated days. Purified rat IgG was used as a control for DTA-1. Data shown in Fig. 1 1 are representative of four independent experiments. By the Kruskal-Wallis ANOVA test, the CT26/NY-ESO-1 growth inhibition by combined treatment with HF10 and DTA-1 was significantly different from the HF10-treated or untreated control at day 42. CMS5a growth inhibition by the HF10 and DTA-1 combination was significantly different from the DTA-1-treated or untreated control at day 25. CMS5a growth inhibition was also significantly different in the HF10-treated group compared with the untreated control.

Mentions: Since the therapeutic efficacy of the adjuvants included in immune-targeting Abs has been widely shown in the treatment of cancer, we hypothesized that the use of DTA-1, as an enhancer of tumor-specific CD8+ T cell responses [26], [27] in HF10 virotherapy might produce a satisfactory treatment outcome. To investigate this hypothesis, we used human NY-ESO-1 gene-transfected CT26 tumor cells (CT26/NY-ESO-1) for in vitro and in vivo studies as an H-2Dd-restricted murine CTL epitope of NY-ESO-1 had been identified in our laboratory [31]. Subcutaneously inoculated CT26/NY-ESO-1 tumors were treated by i.t. administration of HF10 with or without DTA-1 (Fig. 1A). Groups treated with either HF10 or DTA-1 showed weak suppression of tumor growth compared with the untreated group (control), and 2 out of 13 mice (15.4%) or 3 out of 19 mice (15.8%) showed complete tumor regression at 42 days after tumor inoculation, respectively (Table 1). In contrast, all mice in the group treated with both HF10 and DTA-1 showed statistically significant attenuation of tumor growth compared with the control group [p<0.001, Fig. 1A; complete tumor regression rate at 42 days: 60.0% (12 to 20 mice); Table 1]. In addition, CMS5a tumor growth in the group treated with both HF10 and DTA-1 was also suppressed significantly compared with the control or DTA-1-treated groups (Fig. 1B and Table 1).


Systemic CD8+ T cell-mediated tumoricidal effects by intratumoral treatment of oncolytic herpes simplex virus with the agonistic monoclonal antibody for murine glucocorticoid-induced tumor necrosis factor receptor.

Ishihara M, Seo N, Mitsui J, Muraoka D, Tanaka M, Mineno J, Ikeda H, Shiku H - PLoS ONE (2014)

Tumor growth following intratumoral administration of HF10 with/without DTA-1.Growth (mm2) of subcutaneously inoculated CT26/NY-ESO-1 (A) or CMS5a cells (B) following i.t. treatment with HF10 (open triangles) and/or DTA-1 (closed triangles) on indicated days. Purified rat IgG was used as a control for DTA-1. Data shown in Fig. 1 1 are representative of four independent experiments. By the Kruskal-Wallis ANOVA test, the CT26/NY-ESO-1 growth inhibition by combined treatment with HF10 and DTA-1 was significantly different from the HF10-treated or untreated control at day 42. CMS5a growth inhibition by the HF10 and DTA-1 combination was significantly different from the DTA-1-treated or untreated control at day 25. CMS5a growth inhibition was also significantly different in the HF10-treated group compared with the untreated control.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4126744&req=5

pone-0104669-g001: Tumor growth following intratumoral administration of HF10 with/without DTA-1.Growth (mm2) of subcutaneously inoculated CT26/NY-ESO-1 (A) or CMS5a cells (B) following i.t. treatment with HF10 (open triangles) and/or DTA-1 (closed triangles) on indicated days. Purified rat IgG was used as a control for DTA-1. Data shown in Fig. 1 1 are representative of four independent experiments. By the Kruskal-Wallis ANOVA test, the CT26/NY-ESO-1 growth inhibition by combined treatment with HF10 and DTA-1 was significantly different from the HF10-treated or untreated control at day 42. CMS5a growth inhibition by the HF10 and DTA-1 combination was significantly different from the DTA-1-treated or untreated control at day 25. CMS5a growth inhibition was also significantly different in the HF10-treated group compared with the untreated control.
Mentions: Since the therapeutic efficacy of the adjuvants included in immune-targeting Abs has been widely shown in the treatment of cancer, we hypothesized that the use of DTA-1, as an enhancer of tumor-specific CD8+ T cell responses [26], [27] in HF10 virotherapy might produce a satisfactory treatment outcome. To investigate this hypothesis, we used human NY-ESO-1 gene-transfected CT26 tumor cells (CT26/NY-ESO-1) for in vitro and in vivo studies as an H-2Dd-restricted murine CTL epitope of NY-ESO-1 had been identified in our laboratory [31]. Subcutaneously inoculated CT26/NY-ESO-1 tumors were treated by i.t. administration of HF10 with or without DTA-1 (Fig. 1A). Groups treated with either HF10 or DTA-1 showed weak suppression of tumor growth compared with the untreated group (control), and 2 out of 13 mice (15.4%) or 3 out of 19 mice (15.8%) showed complete tumor regression at 42 days after tumor inoculation, respectively (Table 1). In contrast, all mice in the group treated with both HF10 and DTA-1 showed statistically significant attenuation of tumor growth compared with the control group [p<0.001, Fig. 1A; complete tumor regression rate at 42 days: 60.0% (12 to 20 mice); Table 1]. In addition, CMS5a tumor growth in the group treated with both HF10 and DTA-1 was also suppressed significantly compared with the control or DTA-1-treated groups (Fig. 1B and Table 1).

Bottom Line: In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor.The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry.Studies using Fc-digested DTA-1 and Fcγ receptor knockout mice demonstrated the direct participation of DTA-1 in regulatory T cell depletion by antibody-dependent cellular cytotoxicity primarily via macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.

ABSTRACT
Oncolytic virotherapy combined with immunomodulators is a novel noninvasive strategy for cancer treatment. In this study, we examined the tumoricidal effects of oncolytic HF10, a naturally occurring mutant of herpes simplex virus type-1, combined with an agonistic DTA-1 monoclonal antibody specific for the glucocorticoid-induced tumor necrosis factor receptor. Two murine tumor models were used to evaluate the therapeutic efficacies of HF10 virotherapy combined with DTA-1. The kinetics and immunological mechanisms of DTA-1 in HF10 infection were examined using flow cytometry and immunohistochemistry. Intratumoral administration of HF10 in combination with DTA-1 at a low dose resulted in a more vigorous attenuation of growth of the untreated contralateral as well as the treated tumors than treatment with either HF10 or DTA-1 alone. An accumulation of CD8(+) T cells, including tumor- and herpes simplex virus type-1-specific populations, and a decrease in the number of CD4(+) Foxp3(+) T regulatory cells were seen in both HF10- and DTA-1-treated tumors. Studies using Fc-digested DTA-1 and Fcγ receptor knockout mice demonstrated the direct participation of DTA-1 in regulatory T cell depletion by antibody-dependent cellular cytotoxicity primarily via macrophages. These results indicated the potential therapeutic efficacy of a glucocorticoid-induced tumor necrosis factor receptor-specific monoclonal antibody in oncolytic virotherapy at local tumor sites.

Show MeSH
Related in: MedlinePlus