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GK-1 improves the immune response induced by bone marrow dendritic cells loaded with MAGE-AX in mice with melanoma.

Piñón-Zárate G, Herrera-Enríquez MÁ, Hernández-Téllez B, Jarquín-Yáñez K, Castell-Rodríguez AE - J Immunol Res (2014)

Bottom Line: Immunostimulants that could drive a desired immune response are necessary to be found in order to generate a long lasting tumor immune response.Besides, the treatment helped to increase CD8 lymphocytes levels and to produce IFNγ in lymph nodes.Moreover, the histopathological analysis showed that BMDCs treated with GK-1/TNFα and loaded with MAGE-AX induced the apparition of more apoptotic and necrotic areas in tumors than in mice without treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Inmunoterapia e Ingeniería de Tejidos, Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México Edificio A, Sexto Piso, Ciudad Universitaria, Avenida Universidad No. 3000, Ciudad de México 04510DF, Mexico.

ABSTRACT
The aim of dendritic cell (DC) vaccination in cancer is to induce tumor-specific effector T cells that may reduce and control tumor mass. Immunostimulants that could drive a desired immune response are necessary to be found in order to generate a long lasting tumor immune response. GK-1 peptide, derived from Taenia crassiceps, induces not only increase in TNFα, IFNγ, and MCP-1 production in cocultures of DCs and T lymphocytes but also immunological protection against influenza virus. Moreover, the aim of this investigation is the use of GK-1 as a bone marrow DCs (BMDCs) immunostimulant targeted with MAGE antigen; thus, BMDC may be used as immunotherapy against murine melanoma. GK-1 induced in BMDCs a meaningful increment of CD86 and IL-12. In addition, the use of BMDCs TNFα/GK-1/MAGE-AX induced the highest survival and the smallest tumors in mice. Besides, the treatment helped to increase CD8 lymphocytes levels and to produce IFNγ in lymph nodes. Moreover, the histopathological analysis showed that BMDCs treated with GK-1/TNFα and loaded with MAGE-AX induced the apparition of more apoptotic and necrotic areas in tumors than in mice without treatment. These results highlight the properties of GK-1 as an immunostimulant of DCs and suggest as a potential candidate the use of this immunotherapy against cancer disease.

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Histopathological analysis. Photomicrographs of histological sections of tumors from mice vaccinated with BMDCs matured with TNFα and treated with MAGE-AX, GK-1, or MAGE-AX/GK-1. Groups MAGE-AX, GK-1, and MAGE-AX/GK-1 showed plentiful tumor cell death areas. (a) No treatment (WT). Abundant tumor cells and blood vessels were observed. (b) TNFα. The same characteristics as those observed in untreated mice were observed: abundant tumor cells and blood vessels. (c) MAGE-AX. (d) GK-1. (e) MAGE-AX/GK-1. In (c), (d), and (e), pink areas (eosinophilic), composed of dead cells, were observed in addition to purple areas (basophilic), composed of very active tumor cells. (f) A graph showing the change in the areas of cell death in tumors from mice that were treated with BMDCs and which were stimulated with TNFα, MAGE-AX, GK-1, or MAGE-AX/GK-1. ***P < 0.001, ∧P < 0.001 MAGE versus TNF, αP < 0.0001 GK-1 versus TNFα, ɛP < 0.001 MAGE/GK-1 versus TNF. Mean ± SEM n ≥ 3.
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fig6: Histopathological analysis. Photomicrographs of histological sections of tumors from mice vaccinated with BMDCs matured with TNFα and treated with MAGE-AX, GK-1, or MAGE-AX/GK-1. Groups MAGE-AX, GK-1, and MAGE-AX/GK-1 showed plentiful tumor cell death areas. (a) No treatment (WT). Abundant tumor cells and blood vessels were observed. (b) TNFα. The same characteristics as those observed in untreated mice were observed: abundant tumor cells and blood vessels. (c) MAGE-AX. (d) GK-1. (e) MAGE-AX/GK-1. In (c), (d), and (e), pink areas (eosinophilic), composed of dead cells, were observed in addition to purple areas (basophilic), composed of very active tumor cells. (f) A graph showing the change in the areas of cell death in tumors from mice that were treated with BMDCs and which were stimulated with TNFα, MAGE-AX, GK-1, or MAGE-AX/GK-1. ***P < 0.001, ∧P < 0.001 MAGE versus TNF, αP < 0.0001 GK-1 versus TNFα, ɛP < 0.001 MAGE/GK-1 versus TNF. Mean ± SEM n ≥ 3.

Mentions: The histopathological examination of the tumors of the WT mice and from those who received BMDCs treated with TNFα showed abundant epithelioid cell nests, characterized by the presence of many nuclei with abundant euchromatin, which is indicative of a great cellular activity. Also numerous blood vessels between the nests of epithelioid cells were observed (Figures 6(a)-6(b)). Both parameters are related to tumors with a high growth rate [29]. While sections of the tumors from mice that received treatment with MAGE-AX, GK-1, or MAGE-AX/GK-1 BMDCs showed numerous areas of cell death and fewer areas with epithelioid cells than control group, the areas of cell death were characterized by showing eosinophilic regions formed by cellular debris and cells with pyknotic nuclei (Figures 6(c), 6(d), and 6(e)). Afterwards, photographs were taken of the total tumor area, in order to evaluate the percentage of the area of cell death in the tumors (Figure 6(f)). It was observed that the tumors from WT mice and from those who received treatment with TNFα BMDCs were solid tumor masses with few areas of cell death, whereas the tumors from the mice that received therapy with the TNFα/MAGE-AX, TNFα/GK-1, or TNFα/MAGE-AX/GK-1 BMDCs showed larger cell death areas than those from the mice in the control groups and those that received TNFα BMDCs. No significant differences between the TNFα/MAGE, TNFα/GK-1, and TNFα/MAGE/GK-1 groups were found (Figure 6(f)).


GK-1 improves the immune response induced by bone marrow dendritic cells loaded with MAGE-AX in mice with melanoma.

Piñón-Zárate G, Herrera-Enríquez MÁ, Hernández-Téllez B, Jarquín-Yáñez K, Castell-Rodríguez AE - J Immunol Res (2014)

Histopathological analysis. Photomicrographs of histological sections of tumors from mice vaccinated with BMDCs matured with TNFα and treated with MAGE-AX, GK-1, or MAGE-AX/GK-1. Groups MAGE-AX, GK-1, and MAGE-AX/GK-1 showed plentiful tumor cell death areas. (a) No treatment (WT). Abundant tumor cells and blood vessels were observed. (b) TNFα. The same characteristics as those observed in untreated mice were observed: abundant tumor cells and blood vessels. (c) MAGE-AX. (d) GK-1. (e) MAGE-AX/GK-1. In (c), (d), and (e), pink areas (eosinophilic), composed of dead cells, were observed in addition to purple areas (basophilic), composed of very active tumor cells. (f) A graph showing the change in the areas of cell death in tumors from mice that were treated with BMDCs and which were stimulated with TNFα, MAGE-AX, GK-1, or MAGE-AX/GK-1. ***P < 0.001, ∧P < 0.001 MAGE versus TNF, αP < 0.0001 GK-1 versus TNFα, ɛP < 0.001 MAGE/GK-1 versus TNF. Mean ± SEM n ≥ 3.
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Related In: Results  -  Collection

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fig6: Histopathological analysis. Photomicrographs of histological sections of tumors from mice vaccinated with BMDCs matured with TNFα and treated with MAGE-AX, GK-1, or MAGE-AX/GK-1. Groups MAGE-AX, GK-1, and MAGE-AX/GK-1 showed plentiful tumor cell death areas. (a) No treatment (WT). Abundant tumor cells and blood vessels were observed. (b) TNFα. The same characteristics as those observed in untreated mice were observed: abundant tumor cells and blood vessels. (c) MAGE-AX. (d) GK-1. (e) MAGE-AX/GK-1. In (c), (d), and (e), pink areas (eosinophilic), composed of dead cells, were observed in addition to purple areas (basophilic), composed of very active tumor cells. (f) A graph showing the change in the areas of cell death in tumors from mice that were treated with BMDCs and which were stimulated with TNFα, MAGE-AX, GK-1, or MAGE-AX/GK-1. ***P < 0.001, ∧P < 0.001 MAGE versus TNF, αP < 0.0001 GK-1 versus TNFα, ɛP < 0.001 MAGE/GK-1 versus TNF. Mean ± SEM n ≥ 3.
Mentions: The histopathological examination of the tumors of the WT mice and from those who received BMDCs treated with TNFα showed abundant epithelioid cell nests, characterized by the presence of many nuclei with abundant euchromatin, which is indicative of a great cellular activity. Also numerous blood vessels between the nests of epithelioid cells were observed (Figures 6(a)-6(b)). Both parameters are related to tumors with a high growth rate [29]. While sections of the tumors from mice that received treatment with MAGE-AX, GK-1, or MAGE-AX/GK-1 BMDCs showed numerous areas of cell death and fewer areas with epithelioid cells than control group, the areas of cell death were characterized by showing eosinophilic regions formed by cellular debris and cells with pyknotic nuclei (Figures 6(c), 6(d), and 6(e)). Afterwards, photographs were taken of the total tumor area, in order to evaluate the percentage of the area of cell death in the tumors (Figure 6(f)). It was observed that the tumors from WT mice and from those who received treatment with TNFα BMDCs were solid tumor masses with few areas of cell death, whereas the tumors from the mice that received therapy with the TNFα/MAGE-AX, TNFα/GK-1, or TNFα/MAGE-AX/GK-1 BMDCs showed larger cell death areas than those from the mice in the control groups and those that received TNFα BMDCs. No significant differences between the TNFα/MAGE, TNFα/GK-1, and TNFα/MAGE/GK-1 groups were found (Figure 6(f)).

Bottom Line: Immunostimulants that could drive a desired immune response are necessary to be found in order to generate a long lasting tumor immune response.Besides, the treatment helped to increase CD8 lymphocytes levels and to produce IFNγ in lymph nodes.Moreover, the histopathological analysis showed that BMDCs treated with GK-1/TNFα and loaded with MAGE-AX induced the apparition of more apoptotic and necrotic areas in tumors than in mice without treatment.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Inmunoterapia e Ingeniería de Tejidos, Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México Edificio A, Sexto Piso, Ciudad Universitaria, Avenida Universidad No. 3000, Ciudad de México 04510DF, Mexico.

ABSTRACT
The aim of dendritic cell (DC) vaccination in cancer is to induce tumor-specific effector T cells that may reduce and control tumor mass. Immunostimulants that could drive a desired immune response are necessary to be found in order to generate a long lasting tumor immune response. GK-1 peptide, derived from Taenia crassiceps, induces not only increase in TNFα, IFNγ, and MCP-1 production in cocultures of DCs and T lymphocytes but also immunological protection against influenza virus. Moreover, the aim of this investigation is the use of GK-1 as a bone marrow DCs (BMDCs) immunostimulant targeted with MAGE antigen; thus, BMDC may be used as immunotherapy against murine melanoma. GK-1 induced in BMDCs a meaningful increment of CD86 and IL-12. In addition, the use of BMDCs TNFα/GK-1/MAGE-AX induced the highest survival and the smallest tumors in mice. Besides, the treatment helped to increase CD8 lymphocytes levels and to produce IFNγ in lymph nodes. Moreover, the histopathological analysis showed that BMDCs treated with GK-1/TNFα and loaded with MAGE-AX induced the apparition of more apoptotic and necrotic areas in tumors than in mice without treatment. These results highlight the properties of GK-1 as an immunostimulant of DCs and suggest as a potential candidate the use of this immunotherapy against cancer disease.

Show MeSH
Related in: MedlinePlus