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Treatment of tumors with vitamin E suppresses myeloid derived suppressor cells and enhances CD8+ T cell-mediated antitumor effects.

Kang TH, Knoff J, Yeh WH, Yang B, Wang C, Kim YS, Kim TW, Wu TC, Hung CF - PLoS ONE (2014)

Bottom Line: We show that vitamin E alone induces necrosis of TC-1 cells and elicits antitumor effects in TC-1 tumor-bearing mice.We further demonstrate that vitamin E reverses the suppression of T cell activation by MDSCs and that this effect is mediated in part by a nitric oxide-dependent mechanism.Finally, we demonstrate that treatment with vitamin E followed by E7-specific T cell adoptive transfer experience elicits potent antitumor effects in tumor-bearing mice.

View Article: PubMed Central - PubMed

Affiliation: Seoul Department of Immunology, College of Medicine, Konkuk University, Chungju, South Korea.

ABSTRACT
Vitamin E has been shown to have strong anticarcinogenic properties, including antioxidant characteristics, making it an ideal candidate for use in combination with immunotherapies that modify the tumor microenvironment. The tumor microenvironment contains immunosuppressive components, which can be diminished, and immunogenic components, which can be augmented by immunotherapies in order to generate a productive immune response. In the current study, we employ the α-tocopherol succinate isomer of vitamin E to reduce immunosuppression by myeloid derived suppressor cells (MDSCs) as well as adoptive transfer of antigen-specific CD8+ T cells to generate potent antitumor effects against the HPV16 E7-expressing TC-1 tumor model. We show that vitamin E alone induces necrosis of TC-1 cells and elicits antitumor effects in TC-1 tumor-bearing mice. We further demonstrate that vitamin E reverses the suppression of T cell activation by MDSCs and that this effect is mediated in part by a nitric oxide-dependent mechanism. Additionally, treatment with vitamin E reduces the percentage of MDSCs in tumor loci, and induces a higher percentage of T cells, following T cell adoptive transfer. Finally, we demonstrate that treatment with vitamin E followed by E7-specific T cell adoptive transfer experience elicits potent antitumor effects in tumor-bearing mice. Our data provide additional evidence that vitamin E has anticancer properties and that it has promise for use as an adjuvant in combination with a variety of cancer therapies.

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Vitamin E has cytotoxic effect against TC-1 tumor in vitro and in vivo.For the in vitro cytotoxicity experiment, 1×105 TC-1 cells were cultured in 24-well plates. Vitamin E (D-α-tocopherol succinate) (0, 25, 50 µM) was administered 18 hours later and apoptotic (Annexin V+ and 7AAD−) or necrotic (Annexin V+ and 7AAD+) cells were measured using PE labeled Annexin V and 7AAD. (A) Flow cytometry analysis to demonstrate Annexin V+ and 7AAD+ cells. (B) Bar graph depicting the % of Annexin V and 7AAD double positive cells or Annexin V single positive cells. For the in vivo cytotoxicity experiment, 1×105 TC-1 cells were injected into C57BL/6 mice subcutaneously. Beginning on day 10, vitamin E (1 or 2 mg/kg) or DMSO (control) was injected intraperitoneally three times at 2 day intervals. (C) Schematic diagram of the treatment regimen. (D) Line graph depicting growth of TC-1 tumor masses after treatment with vitamin E or DMSO.
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pone-0103562-g001: Vitamin E has cytotoxic effect against TC-1 tumor in vitro and in vivo.For the in vitro cytotoxicity experiment, 1×105 TC-1 cells were cultured in 24-well plates. Vitamin E (D-α-tocopherol succinate) (0, 25, 50 µM) was administered 18 hours later and apoptotic (Annexin V+ and 7AAD−) or necrotic (Annexin V+ and 7AAD+) cells were measured using PE labeled Annexin V and 7AAD. (A) Flow cytometry analysis to demonstrate Annexin V+ and 7AAD+ cells. (B) Bar graph depicting the % of Annexin V and 7AAD double positive cells or Annexin V single positive cells. For the in vivo cytotoxicity experiment, 1×105 TC-1 cells were injected into C57BL/6 mice subcutaneously. Beginning on day 10, vitamin E (1 or 2 mg/kg) or DMSO (control) was injected intraperitoneally three times at 2 day intervals. (C) Schematic diagram of the treatment regimen. (D) Line graph depicting growth of TC-1 tumor masses after treatment with vitamin E or DMSO.

Mentions: We first characterized the antitumor effects toward HPV-16 E7-expressing TC-1 tumor cells generated by vitamin E treatment. TC-1 tumor cells were incubated with 0, 25 or 50 µM vitamin E and subsequently examined for an apoptotic (Annexin V+ and 7AAD−) or necrotic (Annexin V+ and 7AAD+) cell marker profile. Figures 1A and B show that TC-1 cells were increasingly cytotoxic with vitamin E treatment and that treatment with higher vitamin E concentration elicited a higher percentage of necrotic TC-1 cells as opposed to apoptotic cells. To characterize the antitumor effects of vitamin E treatment in vivo, mice were subcutaneously challenged with TC-1 tumor cells and then treated with three injections of vitamin E beginning 10 days later as outlined in Figure 1C. TC-1 tumor-bearing mice experienced increased antitumor effects, as measured by tumor volume, when treated with 2 mg/kg vitamin E compared to control DMSO treatment (Figure 1D). This data indicates that vitamin E is capable of inducing necrosis in TC-1 cells and contributing to tumor control in TC-1 tumor-bearing mice.


Treatment of tumors with vitamin E suppresses myeloid derived suppressor cells and enhances CD8+ T cell-mediated antitumor effects.

Kang TH, Knoff J, Yeh WH, Yang B, Wang C, Kim YS, Kim TW, Wu TC, Hung CF - PLoS ONE (2014)

Vitamin E has cytotoxic effect against TC-1 tumor in vitro and in vivo.For the in vitro cytotoxicity experiment, 1×105 TC-1 cells were cultured in 24-well plates. Vitamin E (D-α-tocopherol succinate) (0, 25, 50 µM) was administered 18 hours later and apoptotic (Annexin V+ and 7AAD−) or necrotic (Annexin V+ and 7AAD+) cells were measured using PE labeled Annexin V and 7AAD. (A) Flow cytometry analysis to demonstrate Annexin V+ and 7AAD+ cells. (B) Bar graph depicting the % of Annexin V and 7AAD double positive cells or Annexin V single positive cells. For the in vivo cytotoxicity experiment, 1×105 TC-1 cells were injected into C57BL/6 mice subcutaneously. Beginning on day 10, vitamin E (1 or 2 mg/kg) or DMSO (control) was injected intraperitoneally three times at 2 day intervals. (C) Schematic diagram of the treatment regimen. (D) Line graph depicting growth of TC-1 tumor masses after treatment with vitamin E or DMSO.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4114790&req=5

pone-0103562-g001: Vitamin E has cytotoxic effect against TC-1 tumor in vitro and in vivo.For the in vitro cytotoxicity experiment, 1×105 TC-1 cells were cultured in 24-well plates. Vitamin E (D-α-tocopherol succinate) (0, 25, 50 µM) was administered 18 hours later and apoptotic (Annexin V+ and 7AAD−) or necrotic (Annexin V+ and 7AAD+) cells were measured using PE labeled Annexin V and 7AAD. (A) Flow cytometry analysis to demonstrate Annexin V+ and 7AAD+ cells. (B) Bar graph depicting the % of Annexin V and 7AAD double positive cells or Annexin V single positive cells. For the in vivo cytotoxicity experiment, 1×105 TC-1 cells were injected into C57BL/6 mice subcutaneously. Beginning on day 10, vitamin E (1 or 2 mg/kg) or DMSO (control) was injected intraperitoneally three times at 2 day intervals. (C) Schematic diagram of the treatment regimen. (D) Line graph depicting growth of TC-1 tumor masses after treatment with vitamin E or DMSO.
Mentions: We first characterized the antitumor effects toward HPV-16 E7-expressing TC-1 tumor cells generated by vitamin E treatment. TC-1 tumor cells were incubated with 0, 25 or 50 µM vitamin E and subsequently examined for an apoptotic (Annexin V+ and 7AAD−) or necrotic (Annexin V+ and 7AAD+) cell marker profile. Figures 1A and B show that TC-1 cells were increasingly cytotoxic with vitamin E treatment and that treatment with higher vitamin E concentration elicited a higher percentage of necrotic TC-1 cells as opposed to apoptotic cells. To characterize the antitumor effects of vitamin E treatment in vivo, mice were subcutaneously challenged with TC-1 tumor cells and then treated with three injections of vitamin E beginning 10 days later as outlined in Figure 1C. TC-1 tumor-bearing mice experienced increased antitumor effects, as measured by tumor volume, when treated with 2 mg/kg vitamin E compared to control DMSO treatment (Figure 1D). This data indicates that vitamin E is capable of inducing necrosis in TC-1 cells and contributing to tumor control in TC-1 tumor-bearing mice.

Bottom Line: We show that vitamin E alone induces necrosis of TC-1 cells and elicits antitumor effects in TC-1 tumor-bearing mice.We further demonstrate that vitamin E reverses the suppression of T cell activation by MDSCs and that this effect is mediated in part by a nitric oxide-dependent mechanism.Finally, we demonstrate that treatment with vitamin E followed by E7-specific T cell adoptive transfer experience elicits potent antitumor effects in tumor-bearing mice.

View Article: PubMed Central - PubMed

Affiliation: Seoul Department of Immunology, College of Medicine, Konkuk University, Chungju, South Korea.

ABSTRACT
Vitamin E has been shown to have strong anticarcinogenic properties, including antioxidant characteristics, making it an ideal candidate for use in combination with immunotherapies that modify the tumor microenvironment. The tumor microenvironment contains immunosuppressive components, which can be diminished, and immunogenic components, which can be augmented by immunotherapies in order to generate a productive immune response. In the current study, we employ the α-tocopherol succinate isomer of vitamin E to reduce immunosuppression by myeloid derived suppressor cells (MDSCs) as well as adoptive transfer of antigen-specific CD8+ T cells to generate potent antitumor effects against the HPV16 E7-expressing TC-1 tumor model. We show that vitamin E alone induces necrosis of TC-1 cells and elicits antitumor effects in TC-1 tumor-bearing mice. We further demonstrate that vitamin E reverses the suppression of T cell activation by MDSCs and that this effect is mediated in part by a nitric oxide-dependent mechanism. Additionally, treatment with vitamin E reduces the percentage of MDSCs in tumor loci, and induces a higher percentage of T cells, following T cell adoptive transfer. Finally, we demonstrate that treatment with vitamin E followed by E7-specific T cell adoptive transfer experience elicits potent antitumor effects in tumor-bearing mice. Our data provide additional evidence that vitamin E has anticancer properties and that it has promise for use as an adjuvant in combination with a variety of cancer therapies.

Show MeSH
Related in: MedlinePlus