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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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Intraperitoneal injection of anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) suppresses the growth of pancreatic cancer tumors. (a) Pan02 cells were inoculated on the right legs in C57BL/6 mice, and 6 days later 100 μg of anti-GITR mAb was intraperitoneally injected into the mice (n = 3). Data are representative of two separate experiments with similar results. (b) The increase of interferon (IFN)-γ-positive cells in response to stimulation of Pan02 cells by an ELISpot assay. Two weeks after the injection of anti-GITR mAb, splenocytes were isolated from treated mice, and co-cultured with Pan02 cells or control lymphocytes (n = 3).
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fig02: Intraperitoneal injection of anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) suppresses the growth of pancreatic cancer tumors. (a) Pan02 cells were inoculated on the right legs in C57BL/6 mice, and 6 days later 100 μg of anti-GITR mAb was intraperitoneally injected into the mice (n = 3). Data are representative of two separate experiments with similar results. (b) The increase of interferon (IFN)-γ-positive cells in response to stimulation of Pan02 cells by an ELISpot assay. Two weeks after the injection of anti-GITR mAb, splenocytes were isolated from treated mice, and co-cultured with Pan02 cells or control lymphocytes (n = 3).

Mentions: To examine whether the blockade of GITR-GITR ligand interaction was able to inhibit the tumor growth of Pan02 subcutaneous tumors, an agonistic anti-GITR mAb (DTA-1: 100 μg) was intraperitoneally injected into the mice with right-leg Pan02 tumors. This significantly suppressed tumor growth as compared with the control IgG injection (Fig. 2a). Then, to examine the expansion of tumor-responsive lymphocytes after the injection of GITR mAb, the splenocytes were harvested 14 days after the antibody administration, and stimulated with MMC-treated Pan02 cells or syngeneic lymphocytes. An ELISpot assay showed that the anti-GITR mAb significantly increased the number of IFN-γ-secreting cells in response to Pan02 cells but not to syngeneic lymphocytes compared with the control IgG treatment (Fig. 2b), suggesting that the blockade of GITR effectively expanded tumor-responsive immune cells.


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)

Intraperitoneal injection of anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) suppresses the growth of pancreatic cancer tumors. (a) Pan02 cells were inoculated on the right legs in C57BL/6 mice, and 6 days later 100 μg of anti-GITR mAb was intraperitoneally injected into the mice (n = 3). Data are representative of two separate experiments with similar results. (b) The increase of interferon (IFN)-γ-positive cells in response to stimulation of Pan02 cells by an ELISpot assay. Two weeks after the injection of anti-GITR mAb, splenocytes were isolated from treated mice, and co-cultured with Pan02 cells or control lymphocytes (n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: Intraperitoneal injection of anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb) suppresses the growth of pancreatic cancer tumors. (a) Pan02 cells were inoculated on the right legs in C57BL/6 mice, and 6 days later 100 μg of anti-GITR mAb was intraperitoneally injected into the mice (n = 3). Data are representative of two separate experiments with similar results. (b) The increase of interferon (IFN)-γ-positive cells in response to stimulation of Pan02 cells by an ELISpot assay. Two weeks after the injection of anti-GITR mAb, splenocytes were isolated from treated mice, and co-cultured with Pan02 cells or control lymphocytes (n = 3).
Mentions: To examine whether the blockade of GITR-GITR ligand interaction was able to inhibit the tumor growth of Pan02 subcutaneous tumors, an agonistic anti-GITR mAb (DTA-1: 100 μg) was intraperitoneally injected into the mice with right-leg Pan02 tumors. This significantly suppressed tumor growth as compared with the control IgG injection (Fig. 2a). Then, to examine the expansion of tumor-responsive lymphocytes after the injection of GITR mAb, the splenocytes were harvested 14 days after the antibody administration, and stimulated with MMC-treated Pan02 cells or syngeneic lymphocytes. An ELISpot assay showed that the anti-GITR mAb significantly increased the number of IFN-γ-secreting cells in response to Pan02 cells but not to syngeneic lymphocytes compared with the control IgG treatment (Fig. 2b), suggesting that the blockade of GITR effectively expanded tumor-responsive immune cells.

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