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Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer.

Aida K, Miyakawa R, Suzuki K, Narumi K, Udagawa T, Yamamoto Y, Chikaraishi T, Yoshida T, Aoki K - Cancer Sci. (2014)

Bottom Line: First we showed that an intraperitoneal administration of an agonistic anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb), which is reported to suppress the function of Tregs, significantly inhibited subcutaneous tumor growth in a murine pancreatic cancer model.The CCR5 expression on Tregs was downregulated in the antibody-treated mice, which may explain the decrease of tumor-infiltrating Tregs.The combination of Treg-suppression by GITR mAb and the tumor immunity induction by IFN-α gene therapy could be a promising therapeutic strategy for pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan; Department of Urology, St. Marianna University, Kanagawa, Japan.

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Anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) enhances the antitumor immunity of intratumoral interferon (IFN)-α gene transfer. Data are representative of at least two separate experiments with similar results. (a) Growth suppression of subcutaneous tumors by anti-GITR mAb and a lower dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 1 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 8). (b) Antitumor effect by anti-GITR mAb and a higher dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 5 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 10). (c) Growth suppression of CT26 subcutaneous tumors by anti-GITR mAb and Ad-mIFN. CT26 cells were inoculated on right legs in BALB/c mice. The 30 μg of GITR mAb was intrepertioneally injected once at day 8, and then 3 × 107 PFU of Ad-mIFN or Ad-AP were injected once into the tumors at day 11 (n = 9). (d) Growth of different tumors by a combination therapy. Pan02 cells were inoculated on right legs and CT26 cells were inoculated on left legs in (C57BL/6 × BALB/c) F1 mice. The 30 μg of anti-GITR mAb antibody was intraperitoneally injected into the mice at day 6, and 5 × 107 PFU of Ad-mIFN was injected into the right Pan02 tumors at day 11.
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fig03: Anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) enhances the antitumor immunity of intratumoral interferon (IFN)-α gene transfer. Data are representative of at least two separate experiments with similar results. (a) Growth suppression of subcutaneous tumors by anti-GITR mAb and a lower dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 1 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 8). (b) Antitumor effect by anti-GITR mAb and a higher dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 5 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 10). (c) Growth suppression of CT26 subcutaneous tumors by anti-GITR mAb and Ad-mIFN. CT26 cells were inoculated on right legs in BALB/c mice. The 30 μg of GITR mAb was intrepertioneally injected once at day 8, and then 3 × 107 PFU of Ad-mIFN or Ad-AP were injected once into the tumors at day 11 (n = 9). (d) Growth of different tumors by a combination therapy. Pan02 cells were inoculated on right legs and CT26 cells were inoculated on left legs in (C57BL/6 × BALB/c) F1 mice. The 30 μg of anti-GITR mAb antibody was intraperitoneally injected into the mice at day 6, and 5 × 107 PFU of Ad-mIFN was injected into the right Pan02 tumors at day 11.

Mentions: To ascertain whether the combination of anti-GITR mAb enhances an antitumor immunity induced by the intratumoral IFN-α gene transfer, the antibody was intrapertitoneally administered at day 6 after the subcutaneous inoculation of Pan02 cells followed by intratumoral injection of Ad-mIFN at day 11. The injection of a lower dose (1 × 107 PFU) of Ad-mIFN showed the tumor suppressive effects not only in vector-injected right tumors but also in the vector-uninjected left tumors in anti-GITR mAb-treated mice compared with the injection of Ad-AP (Fig. 3a). Furthermore, the higher dose (5 × 107 PFU) of Ad-mIFN with anti-GITR mAb showed the stronger suppressive effect of Pan02 tumor growth at both sites compared with the lower dose adenovirus injection (Fig. 3b).


Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer.

Aida K, Miyakawa R, Suzuki K, Narumi K, Udagawa T, Yamamoto Y, Chikaraishi T, Yoshida T, Aoki K - Cancer Sci. (2014)

Anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) enhances the antitumor immunity of intratumoral interferon (IFN)-α gene transfer. Data are representative of at least two separate experiments with similar results. (a) Growth suppression of subcutaneous tumors by anti-GITR mAb and a lower dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 1 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 8). (b) Antitumor effect by anti-GITR mAb and a higher dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 5 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 10). (c) Growth suppression of CT26 subcutaneous tumors by anti-GITR mAb and Ad-mIFN. CT26 cells were inoculated on right legs in BALB/c mice. The 30 μg of GITR mAb was intrepertioneally injected once at day 8, and then 3 × 107 PFU of Ad-mIFN or Ad-AP were injected once into the tumors at day 11 (n = 9). (d) Growth of different tumors by a combination therapy. Pan02 cells were inoculated on right legs and CT26 cells were inoculated on left legs in (C57BL/6 × BALB/c) F1 mice. The 30 μg of anti-GITR mAb antibody was intraperitoneally injected into the mice at day 6, and 5 × 107 PFU of Ad-mIFN was injected into the right Pan02 tumors at day 11.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317823&req=5

fig03: Anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) enhances the antitumor immunity of intratumoral interferon (IFN)-α gene transfer. Data are representative of at least two separate experiments with similar results. (a) Growth suppression of subcutaneous tumors by anti-GITR mAb and a lower dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 1 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 8). (b) Antitumor effect by anti-GITR mAb and a higher dose of Ad-mIFN. Pan02 cells were inoculated on both legs in C57BL/6 mice. The 100 μg of GITR mAb was intrapertioneally injected once at day 6, and then 5 × 107 PFU of Ad-mIFN or Ad-AP was injected once into the tumors at day 11 (n = 10). (c) Growth suppression of CT26 subcutaneous tumors by anti-GITR mAb and Ad-mIFN. CT26 cells were inoculated on right legs in BALB/c mice. The 30 μg of GITR mAb was intrepertioneally injected once at day 8, and then 3 × 107 PFU of Ad-mIFN or Ad-AP were injected once into the tumors at day 11 (n = 9). (d) Growth of different tumors by a combination therapy. Pan02 cells were inoculated on right legs and CT26 cells were inoculated on left legs in (C57BL/6 × BALB/c) F1 mice. The 30 μg of anti-GITR mAb antibody was intraperitoneally injected into the mice at day 6, and 5 × 107 PFU of Ad-mIFN was injected into the right Pan02 tumors at day 11.
Mentions: To ascertain whether the combination of anti-GITR mAb enhances an antitumor immunity induced by the intratumoral IFN-α gene transfer, the antibody was intrapertitoneally administered at day 6 after the subcutaneous inoculation of Pan02 cells followed by intratumoral injection of Ad-mIFN at day 11. The injection of a lower dose (1 × 107 PFU) of Ad-mIFN showed the tumor suppressive effects not only in vector-injected right tumors but also in the vector-uninjected left tumors in anti-GITR mAb-treated mice compared with the injection of Ad-AP (Fig. 3a). Furthermore, the higher dose (5 × 107 PFU) of Ad-mIFN with anti-GITR mAb showed the stronger suppressive effect of Pan02 tumor growth at both sites compared with the lower dose adenovirus injection (Fig. 3b).

Bottom Line: First we showed that an intraperitoneal administration of an agonistic anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb), which is reported to suppress the function of Tregs, significantly inhibited subcutaneous tumor growth in a murine pancreatic cancer model.The CCR5 expression on Tregs was downregulated in the antibody-treated mice, which may explain the decrease of tumor-infiltrating Tregs.The combination of Treg-suppression by GITR mAb and the tumor immunity induction by IFN-α gene therapy could be a promising therapeutic strategy for pancreatic cancer.

View Article: PubMed Central - PubMed

Affiliation: Division of Gene and Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan; Department of Urology, St. Marianna University, Kanagawa, Japan.

Show MeSH
Related in: MedlinePlus