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Combining TGF-β1 knockdown and miR200c administration to optimize antitumor efficacy of B16F10/GPI-IL-21 vaccine.

Wang X, Zhao F, He X, Wang J, Zhang Y, Zhang H, Ni Y, Sun J, Wang X, Dou J - Oncotarget (2015)

Bottom Line: Our study aimed at optimizing the antitumor effects of the B16F10/glycosylphosphatidylinositol-interleukin 21 (B16F10/GPI-IL-21) tumor vaccine on melanoma bearing mice by combining the TGF-β1 knockdown and the administration of miR200c agomir.The later combination showed that, when compared with the mice in the control group that received no vaccination, vaccinated mice significantly increased NK and CTL activities, enhanced levels of IFN-γ, and reduced expression of TGF-β1, N-cadherin, Vimentin, Gli1/2, P-Smad2/3 and others involved in promoting expression of EMT-related molecules in tumor areas, and inhibited the melanoma metastasis in lungs and lymph nodes.Altogether, our findings demonstrate that this synergistic anti-cancer regimen effectively induces strong immune response and diminishes the melanoma progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathogenic Biology and Immunology, School of Medicine & Collaborative Innovation Center of Suzhou Nano Science and Technology, Southeast University, Nanjing, China.

ABSTRACT
TGF-β1 secreted abundantly by tumors cells as well as present in the local microenvironment promotes neoplasm invasion and metastasis by triggering the epithelial to mesenchymal transition (EMT). MiR200c has been shown to suppress EMT and to regulate the cellular epithelial and interstitial state conversion, whereas the tumor vaccines are intended to specifically initiate or amplify a host response against evolving tumor cells. Our study aimed at optimizing the antitumor effects of the B16F10/glycosylphosphatidylinositol-interleukin 21 (B16F10/GPI-IL-21) tumor vaccine on melanoma bearing mice by combining the TGF-β1 knockdown and the administration of miR200c agomir. The mice were subcutaneously vaccinated with inactivated B16F10/GPI-IL-21 vaccine and challenged by B16F10 cells transfected with shTGF-β1 (B16F10/shTGF-β1 cells) or B16F10/shTGF-β1 cells with the administration of miR200c agomir. The later combination showed that, when compared with the mice in the control group that received no vaccination, vaccinated mice significantly increased NK and CTL activities, enhanced levels of IFN-γ, and reduced expression of TGF-β1, N-cadherin, Vimentin, Gli1/2, P-Smad2/3 and others involved in promoting expression of EMT-related molecules in tumor areas, and inhibited the melanoma metastasis in lungs and lymph nodes. Altogether, our findings demonstrate that this synergistic anti-cancer regimen effectively induces strong immune response and diminishes the melanoma progression.

No MeSH data available.


Related in: MedlinePlus

The activities of CTL and NK and CD4+CD25+Treg cell level in vaccinated mice challenged with B16F10/shTGF-β1 cellsA and B. The CTL and NK cytotoxic activities were analyzed by Flow Cytometry for the differently treated groups, and the quantification analysis was shown in C, D and E. The level of CD4+CD25+Treg cells was analyzed by a Flow Cytometry in splenocytes (D) and tumor draining lymph nodes (E); refer to the statistical differences as shown in F. n=9.
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Figure 4: The activities of CTL and NK and CD4+CD25+Treg cell level in vaccinated mice challenged with B16F10/shTGF-β1 cellsA and B. The CTL and NK cytotoxic activities were analyzed by Flow Cytometry for the differently treated groups, and the quantification analysis was shown in C, D and E. The level of CD4+CD25+Treg cells was analyzed by a Flow Cytometry in splenocytes (D) and tumor draining lymph nodes (E); refer to the statistical differences as shown in F. n=9.

Mentions: Further, we evaluated the splenocyte cytotoxicity to the B16F10 cells or to the YAC-1 cells, which represents to the CTL or NK activity. The results showed that the B16F10/GPI-IL-21 combined with the down-regulated TGF-β1 and the administration of miR200c agomir group remarkably enhanced the CTL and NK cytotoxic activities in comparison with any other groups (Figure 4A and 4B); the differences were statistically significant (Figure 4C). In addition, the CD4+CD25+Treg cells derived from the splenocytes and tumor draining lymph nodes were significantly reduced in the tumor vaccine in combination with shTGF-β1 and miR200c group as shown in Figure 4D, 4E and 4F; these findings suggested that the multiple immune effects were induced through using the tumor vaccine B16F10/GPI-IL-21 combined with the down- regulated TGF-β1 and the administration of miR200c agomir.


Combining TGF-β1 knockdown and miR200c administration to optimize antitumor efficacy of B16F10/GPI-IL-21 vaccine.

Wang X, Zhao F, He X, Wang J, Zhang Y, Zhang H, Ni Y, Sun J, Wang X, Dou J - Oncotarget (2015)

The activities of CTL and NK and CD4+CD25+Treg cell level in vaccinated mice challenged with B16F10/shTGF-β1 cellsA and B. The CTL and NK cytotoxic activities were analyzed by Flow Cytometry for the differently treated groups, and the quantification analysis was shown in C, D and E. The level of CD4+CD25+Treg cells was analyzed by a Flow Cytometry in splenocytes (D) and tumor draining lymph nodes (E); refer to the statistical differences as shown in F. n=9.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494953&req=5

Figure 4: The activities of CTL and NK and CD4+CD25+Treg cell level in vaccinated mice challenged with B16F10/shTGF-β1 cellsA and B. The CTL and NK cytotoxic activities were analyzed by Flow Cytometry for the differently treated groups, and the quantification analysis was shown in C, D and E. The level of CD4+CD25+Treg cells was analyzed by a Flow Cytometry in splenocytes (D) and tumor draining lymph nodes (E); refer to the statistical differences as shown in F. n=9.
Mentions: Further, we evaluated the splenocyte cytotoxicity to the B16F10 cells or to the YAC-1 cells, which represents to the CTL or NK activity. The results showed that the B16F10/GPI-IL-21 combined with the down-regulated TGF-β1 and the administration of miR200c agomir group remarkably enhanced the CTL and NK cytotoxic activities in comparison with any other groups (Figure 4A and 4B); the differences were statistically significant (Figure 4C). In addition, the CD4+CD25+Treg cells derived from the splenocytes and tumor draining lymph nodes were significantly reduced in the tumor vaccine in combination with shTGF-β1 and miR200c group as shown in Figure 4D, 4E and 4F; these findings suggested that the multiple immune effects were induced through using the tumor vaccine B16F10/GPI-IL-21 combined with the down- regulated TGF-β1 and the administration of miR200c agomir.

Bottom Line: Our study aimed at optimizing the antitumor effects of the B16F10/glycosylphosphatidylinositol-interleukin 21 (B16F10/GPI-IL-21) tumor vaccine on melanoma bearing mice by combining the TGF-β1 knockdown and the administration of miR200c agomir.The later combination showed that, when compared with the mice in the control group that received no vaccination, vaccinated mice significantly increased NK and CTL activities, enhanced levels of IFN-γ, and reduced expression of TGF-β1, N-cadherin, Vimentin, Gli1/2, P-Smad2/3 and others involved in promoting expression of EMT-related molecules in tumor areas, and inhibited the melanoma metastasis in lungs and lymph nodes.Altogether, our findings demonstrate that this synergistic anti-cancer regimen effectively induces strong immune response and diminishes the melanoma progression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathogenic Biology and Immunology, School of Medicine & Collaborative Innovation Center of Suzhou Nano Science and Technology, Southeast University, Nanjing, China.

ABSTRACT
TGF-β1 secreted abundantly by tumors cells as well as present in the local microenvironment promotes neoplasm invasion and metastasis by triggering the epithelial to mesenchymal transition (EMT). MiR200c has been shown to suppress EMT and to regulate the cellular epithelial and interstitial state conversion, whereas the tumor vaccines are intended to specifically initiate or amplify a host response against evolving tumor cells. Our study aimed at optimizing the antitumor effects of the B16F10/glycosylphosphatidylinositol-interleukin 21 (B16F10/GPI-IL-21) tumor vaccine on melanoma bearing mice by combining the TGF-β1 knockdown and the administration of miR200c agomir. The mice were subcutaneously vaccinated with inactivated B16F10/GPI-IL-21 vaccine and challenged by B16F10 cells transfected with shTGF-β1 (B16F10/shTGF-β1 cells) or B16F10/shTGF-β1 cells with the administration of miR200c agomir. The later combination showed that, when compared with the mice in the control group that received no vaccination, vaccinated mice significantly increased NK and CTL activities, enhanced levels of IFN-γ, and reduced expression of TGF-β1, N-cadherin, Vimentin, Gli1/2, P-Smad2/3 and others involved in promoting expression of EMT-related molecules in tumor areas, and inhibited the melanoma metastasis in lungs and lymph nodes. Altogether, our findings demonstrate that this synergistic anti-cancer regimen effectively induces strong immune response and diminishes the melanoma progression.

No MeSH data available.


Related in: MedlinePlus