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Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma.

Markov OV, Mironova NL, Sennikov SV, Vlassov VV, Zenkova MA - PLoS ONE (2015)

Bottom Line: Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection.Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found.In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless the antimetastatic effect was less effective in comparison with prophylactic DC vaccine.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia.

ABSTRACT
Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless the antimetastatic effect was less effective in comparison with prophylactic DC vaccine.

No MeSH data available.


Related in: MedlinePlus

Anti-tumour and anti-metastatic effects of DC vaccination under prophylactic and therapeutic schemes.A and B. Krebs-2 adenocarcinoma growth retardation after treatment with DC vaccines. w/t—non-treated mice with Krebs-2 injected with saline buffer. C and D. LLC tumor growth retardation and suppression of metastasis after treatment with DC vaccines. For A-D type of DC vaccine is presented as S/T/A—Scheme/ Transfectant/ Antigen source. w/t—non-treated mice with LLC injected with saline buffer. E. Suppression of B16 melanoma metastasis after treatment with DC vaccines. For E type of DC vaccine is presented as S-I/T/A—Scheme—Immunization number/ Transfectant/ Antigen source. w/t—non-treated mice with metastatic melanoma injected with saline buffer. Data were statistically analysed using one-way ANOVA with post hoc Fisher test. Data are presented as mean±S.E.M. p value <0.05 was considered to be statistically significant. Scheme 1: Healthy mice received i.v. DC vaccines according to presented S/T/A type. On day 7 after DC vaccination tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot. In the case of B16 model healthy mice received i.v. Dc vaccines according to presented S-I/T/A type: on day 7 before tumor transplantation (S-I: 1–1) and on day 14 and 7 before tumor transplantation (S-I:1–2). B16 was induced by transplantation of B16 cells (105 cells/mouse) into lateral tail vein. Scheme 2. Tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot or intravenous inoculation of B16 cells (105 cells/mouse) into lateral tail vein. On day 4 after tumor transplantation mice received i.v. Dc vaccines according to presented S/T/A or S-I/T/A type.
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pone.0136911.g003: Anti-tumour and anti-metastatic effects of DC vaccination under prophylactic and therapeutic schemes.A and B. Krebs-2 adenocarcinoma growth retardation after treatment with DC vaccines. w/t—non-treated mice with Krebs-2 injected with saline buffer. C and D. LLC tumor growth retardation and suppression of metastasis after treatment with DC vaccines. For A-D type of DC vaccine is presented as S/T/A—Scheme/ Transfectant/ Antigen source. w/t—non-treated mice with LLC injected with saline buffer. E. Suppression of B16 melanoma metastasis after treatment with DC vaccines. For E type of DC vaccine is presented as S-I/T/A—Scheme—Immunization number/ Transfectant/ Antigen source. w/t—non-treated mice with metastatic melanoma injected with saline buffer. Data were statistically analysed using one-way ANOVA with post hoc Fisher test. Data are presented as mean±S.E.M. p value <0.05 was considered to be statistically significant. Scheme 1: Healthy mice received i.v. DC vaccines according to presented S/T/A type. On day 7 after DC vaccination tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot. In the case of B16 model healthy mice received i.v. Dc vaccines according to presented S-I/T/A type: on day 7 before tumor transplantation (S-I: 1–1) and on day 14 and 7 before tumor transplantation (S-I:1–2). B16 was induced by transplantation of B16 cells (105 cells/mouse) into lateral tail vein. Scheme 2. Tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot or intravenous inoculation of B16 cells (105 cells/mouse) into lateral tail vein. On day 4 after tumor transplantation mice received i.v. Dc vaccines according to presented S/T/A or S-I/T/A type.

Mentions: The anti-tumor effects of prophylactic and therapeutic vaccinations are presented in Fig 3. DC vaccination with the prophylactic scheme did not affect tumor growth regardless of the antigen source (lysate or total RNA). Our data show that in the Krebs-2 model the highest anti-tumor activity was observed in the case of therapeutic vaccination (Fig 3B). Administration of the DC vaccine under Scheme 2 resulted in discernible inhibition of tumor growth: in the group of mice treated with 1/LF/RNA DC vaccine (abbreviation corresponds to Scheme of the treatment/ Transfectant/ Antigen source), tumor size was decreased 1.9-fold in comparison with the control group (p = 0.036, Fig 3B). Administration of 2/lysate under the therapeutic scheme did not lead to an apparent retardation of tumor growth in comparison with the control group and the group treated with 1/LF.


Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma.

Markov OV, Mironova NL, Sennikov SV, Vlassov VV, Zenkova MA - PLoS ONE (2015)

Anti-tumour and anti-metastatic effects of DC vaccination under prophylactic and therapeutic schemes.A and B. Krebs-2 adenocarcinoma growth retardation after treatment with DC vaccines. w/t—non-treated mice with Krebs-2 injected with saline buffer. C and D. LLC tumor growth retardation and suppression of metastasis after treatment with DC vaccines. For A-D type of DC vaccine is presented as S/T/A—Scheme/ Transfectant/ Antigen source. w/t—non-treated mice with LLC injected with saline buffer. E. Suppression of B16 melanoma metastasis after treatment with DC vaccines. For E type of DC vaccine is presented as S-I/T/A—Scheme—Immunization number/ Transfectant/ Antigen source. w/t—non-treated mice with metastatic melanoma injected with saline buffer. Data were statistically analysed using one-way ANOVA with post hoc Fisher test. Data are presented as mean±S.E.M. p value <0.05 was considered to be statistically significant. Scheme 1: Healthy mice received i.v. DC vaccines according to presented S/T/A type. On day 7 after DC vaccination tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot. In the case of B16 model healthy mice received i.v. Dc vaccines according to presented S-I/T/A type: on day 7 before tumor transplantation (S-I: 1–1) and on day 14 and 7 before tumor transplantation (S-I:1–2). B16 was induced by transplantation of B16 cells (105 cells/mouse) into lateral tail vein. Scheme 2. Tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot or intravenous inoculation of B16 cells (105 cells/mouse) into lateral tail vein. On day 4 after tumor transplantation mice received i.v. Dc vaccines according to presented S/T/A or S-I/T/A type.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4556596&req=5

pone.0136911.g003: Anti-tumour and anti-metastatic effects of DC vaccination under prophylactic and therapeutic schemes.A and B. Krebs-2 adenocarcinoma growth retardation after treatment with DC vaccines. w/t—non-treated mice with Krebs-2 injected with saline buffer. C and D. LLC tumor growth retardation and suppression of metastasis after treatment with DC vaccines. For A-D type of DC vaccine is presented as S/T/A—Scheme/ Transfectant/ Antigen source. w/t—non-treated mice with LLC injected with saline buffer. E. Suppression of B16 melanoma metastasis after treatment with DC vaccines. For E type of DC vaccine is presented as S-I/T/A—Scheme—Immunization number/ Transfectant/ Antigen source. w/t—non-treated mice with metastatic melanoma injected with saline buffer. Data were statistically analysed using one-way ANOVA with post hoc Fisher test. Data are presented as mean±S.E.M. p value <0.05 was considered to be statistically significant. Scheme 1: Healthy mice received i.v. DC vaccines according to presented S/T/A type. On day 7 after DC vaccination tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot. In the case of B16 model healthy mice received i.v. Dc vaccines according to presented S-I/T/A type: on day 7 before tumor transplantation (S-I: 1–1) and on day 14 and 7 before tumor transplantation (S-I:1–2). B16 was induced by transplantation of B16 cells (105 cells/mouse) into lateral tail vein. Scheme 2. Tumors were induced in mice by intramuscular injection of Krebs-2 cells (105 cells/mouse) or LLC cells (6×105 cells/mouse) into the femur muscle of right hindfoot or intravenous inoculation of B16 cells (105 cells/mouse) into lateral tail vein. On day 4 after tumor transplantation mice received i.v. Dc vaccines according to presented S/T/A or S-I/T/A type.
Mentions: The anti-tumor effects of prophylactic and therapeutic vaccinations are presented in Fig 3. DC vaccination with the prophylactic scheme did not affect tumor growth regardless of the antigen source (lysate or total RNA). Our data show that in the Krebs-2 model the highest anti-tumor activity was observed in the case of therapeutic vaccination (Fig 3B). Administration of the DC vaccine under Scheme 2 resulted in discernible inhibition of tumor growth: in the group of mice treated with 1/LF/RNA DC vaccine (abbreviation corresponds to Scheme of the treatment/ Transfectant/ Antigen source), tumor size was decreased 1.9-fold in comparison with the control group (p = 0.036, Fig 3B). Administration of 2/lysate under the therapeutic scheme did not lead to an apparent retardation of tumor growth in comparison with the control group and the group treated with 1/LF.

Bottom Line: Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection.Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found.In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless the antimetastatic effect was less effective in comparison with prophylactic DC vaccine.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of Russian Academy of Sciences, Novosibirsk, Russia.

ABSTRACT
Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless the antimetastatic effect was less effective in comparison with prophylactic DC vaccine.

No MeSH data available.


Related in: MedlinePlus