Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil
Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently...
Ausführliche Beschreibung
Autor*in: |
Wang, Xiaodong [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2018 |
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Anmerkung: |
© The Author(s) 2018 |
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Übergeordnetes Werk: |
Enthalten in: Journal of translational medicine - London : BioMed Central, 2003, 16(2018), 1 vom: 08. Mai |
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Übergeordnetes Werk: |
volume:16 ; year:2018 ; number:1 ; day:08 ; month:05 |
Links: |
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DOI / URN: |
10.1186/s12967-018-1501-z |
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Katalog-ID: |
SPR028967410 |
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520 | |a Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. | ||
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700 | 1 | |a Diao, Yuwen |4 aut | |
700 | 1 | |a Gao, Ningning |4 aut | |
700 | 1 | |a Wan, Yanyan |4 aut | |
700 | 1 | |a Zhong, Jingjing |4 aut | |
700 | 1 | |a Zheng, Huali |4 aut | |
700 | 1 | |a Wang, Zhulin |4 aut | |
700 | 1 | |a Jin, Guangyi |4 aut | |
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10.1186/s12967-018-1501-z doi (DE-627)SPR028967410 (SPR)s12967-018-1501-z-e DE-627 ger DE-627 rakwb eng Wang, Xiaodong verfasserin (orcid)0000-0003-2564-8041 aut Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. Gastric cancer (dpeaa)DE-He213 Vaccine (dpeaa)DE-He213 TLR7 (dpeaa)DE-He213 MG7-Ag (dpeaa)DE-He213 5-Fluorouracil (dpeaa)DE-He213 Liu, Yu aut Diao, Yuwen aut Gao, Ningning aut Wan, Yanyan aut Zhong, Jingjing aut Zheng, Huali aut Wang, Zhulin aut Jin, Guangyi aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 08. Mai (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:08 month:05 https://dx.doi.org/10.1186/s12967-018-1501-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 08 05 |
spelling |
10.1186/s12967-018-1501-z doi (DE-627)SPR028967410 (SPR)s12967-018-1501-z-e DE-627 ger DE-627 rakwb eng Wang, Xiaodong verfasserin (orcid)0000-0003-2564-8041 aut Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. Gastric cancer (dpeaa)DE-He213 Vaccine (dpeaa)DE-He213 TLR7 (dpeaa)DE-He213 MG7-Ag (dpeaa)DE-He213 5-Fluorouracil (dpeaa)DE-He213 Liu, Yu aut Diao, Yuwen aut Gao, Ningning aut Wan, Yanyan aut Zhong, Jingjing aut Zheng, Huali aut Wang, Zhulin aut Jin, Guangyi aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 08. Mai (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:08 month:05 https://dx.doi.org/10.1186/s12967-018-1501-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 08 05 |
allfields_unstemmed |
10.1186/s12967-018-1501-z doi (DE-627)SPR028967410 (SPR)s12967-018-1501-z-e DE-627 ger DE-627 rakwb eng Wang, Xiaodong verfasserin (orcid)0000-0003-2564-8041 aut Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. Gastric cancer (dpeaa)DE-He213 Vaccine (dpeaa)DE-He213 TLR7 (dpeaa)DE-He213 MG7-Ag (dpeaa)DE-He213 5-Fluorouracil (dpeaa)DE-He213 Liu, Yu aut Diao, Yuwen aut Gao, Ningning aut Wan, Yanyan aut Zhong, Jingjing aut Zheng, Huali aut Wang, Zhulin aut Jin, Guangyi aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 08. Mai (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:08 month:05 https://dx.doi.org/10.1186/s12967-018-1501-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 08 05 |
allfieldsGer |
10.1186/s12967-018-1501-z doi (DE-627)SPR028967410 (SPR)s12967-018-1501-z-e DE-627 ger DE-627 rakwb eng Wang, Xiaodong verfasserin (orcid)0000-0003-2564-8041 aut Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. Gastric cancer (dpeaa)DE-He213 Vaccine (dpeaa)DE-He213 TLR7 (dpeaa)DE-He213 MG7-Ag (dpeaa)DE-He213 5-Fluorouracil (dpeaa)DE-He213 Liu, Yu aut Diao, Yuwen aut Gao, Ningning aut Wan, Yanyan aut Zhong, Jingjing aut Zheng, Huali aut Wang, Zhulin aut Jin, Guangyi aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 08. Mai (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:08 month:05 https://dx.doi.org/10.1186/s12967-018-1501-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 08 05 |
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10.1186/s12967-018-1501-z doi (DE-627)SPR028967410 (SPR)s12967-018-1501-z-e DE-627 ger DE-627 rakwb eng Wang, Xiaodong verfasserin (orcid)0000-0003-2564-8041 aut Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. Gastric cancer (dpeaa)DE-He213 Vaccine (dpeaa)DE-He213 TLR7 (dpeaa)DE-He213 MG7-Ag (dpeaa)DE-He213 5-Fluorouracil (dpeaa)DE-He213 Liu, Yu aut Diao, Yuwen aut Gao, Ningning aut Wan, Yanyan aut Zhong, Jingjing aut Zheng, Huali aut Wang, Zhulin aut Jin, Guangyi aut Enthalten in Journal of translational medicine London : BioMed Central, 2003 16(2018), 1 vom: 08. Mai (DE-627)369084136 (DE-600)2118570-0 1479-5876 nnns volume:16 year:2018 number:1 day:08 month:05 https://dx.doi.org/10.1186/s12967-018-1501-z kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 16 2018 1 08 05 |
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Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil |
abstract |
Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. © The Author(s) 2018 |
abstractGer |
Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. © The Author(s) 2018 |
abstract_unstemmed |
Background Vaccines play increasingly important roles in cancer treatment due to their advantages of effective targeting and few side effects. Our laboratory has attempted to construct vaccines by conjugating TLR7 agonists with tumor-associated antigens. Furthermore, immunochemotherapy has recently become an appealing approach to cancer therapy. 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent, can reportedly potently and selectively kill tumor-associated MDSCs in vivo. Methods Gastric cancer vaccines were synthesized by the covalent attachment of our TLR7 agonist with the gastric cancer antigen MG7-Ag tetra-epitope, leading to T7 − ML (linear tetra-epitope) and T7 − MB (branched tetra-epitope). Cytokines induced by the vaccines in vitro were assessed by ELISA. A tumor challenge model was created by treating BALB/c mice on either a prophylactic or therapeutic vaccination schedule. 5-FU was simultaneously applied to mice in the combination treatment group. CTL and ADCC activities were determined by the LDH method, while $ CD3^{+} $/$ CD8^{+} $, $ CD3^{+} $/$ CD4^{+} $ T cells and MDSCs were evaluated by flow cytometry. Results In vitro, rapid TNF-α and IL-12 inductions occurred in BMDCs treated with the vaccines. In vivo, among all the vaccines tested, T7 − MB most effectively reduced EAC tumor burdens and induced CTLs, antibodies and ADCC activity in BALB/c mice. Immunization with T7 − MB in combination with 5-FU chemotherapy reduced tumor sizes and extended long-term survival rates, mainly by improving T cell responses, including CTLs, $ CD3^{+} $/$ CD8^{+} $ and $ CD3^{+} $/$ CD4^{+} $ T cells. 5-FU also enhanced the T7 − MB efficiency by reversing immunosuppressive factors, i.e., MDSCs, which could not be validly inhibited by the vaccines alone. In addition, T7 − MB repressed tumor growth and immune tolerance when the therapeutic schedule was used, although the effects were weaker than those achieved with either T7 − MB alone or in combination with 5-FU on the prophylactic schedule. Conclusions A novel effective gastric cancer vaccine was constructed, and the importance of branched multiple antigen peptides and chemical conjugation to vaccine design were confirmed. The synergistic effects and mechanisms of T7 − MB and 5-FU were also established, observing mainly T cell activation and MDSC inhibition. © The Author(s) 2018 |
collection_details |
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container_issue |
1 |
title_short |
Gastric cancer vaccines synthesized using a TLR7 agonist and their synergistic antitumor effects with 5-fluorouracil |
url |
https://dx.doi.org/10.1186/s12967-018-1501-z |
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Liu, Yu Diao, Yuwen Gao, Ningning Wan, Yanyan Zhong, Jingjing Zheng, Huali Wang, Zhulin Jin, Guangyi |
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Liu, Yu Diao, Yuwen Gao, Ningning Wan, Yanyan Zhong, Jingjing Zheng, Huali Wang, Zhulin Jin, Guangyi |
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up_date |
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