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An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy
PURPOSE: Recent studies have shown that a new generation of synthetic agonist of Toll-like receptor (TLR) 9 consisting a 3′-3′-attached structure and a dCp7-deaza-dG dinucultodie shows more potent immunostimulatory effects in both mouse and human than conventional CpG oligonucleotides. Radiation the...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364192/ https://www.ncbi.nlm.nih.gov/pubmed/22666458 http://dx.doi.org/10.1371/journal.pone.0038111 |
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author | Zhang, Huagang Liu, Laibin Yu, Dong Kandimalla, Ekambar R. Sun, Hui Bin Agrawal, Sudhir Guha, Chandan |
author_facet | Zhang, Huagang Liu, Laibin Yu, Dong Kandimalla, Ekambar R. Sun, Hui Bin Agrawal, Sudhir Guha, Chandan |
author_sort | Zhang, Huagang |
collection | PubMed |
description | PURPOSE: Recent studies have shown that a new generation of synthetic agonist of Toll-like receptor (TLR) 9 consisting a 3′-3′-attached structure and a dCp7-deaza-dG dinucultodie shows more potent immunostimulatory effects in both mouse and human than conventional CpG oligonucleotides. Radiation therapy (RT) provides a source of tumor antigens that are released from dying, irradiated, tumor cells without causing systemic immunosuppression. We, therefore, examined effect of combining RT with a designer synthetic agonist of TLR9 on anti-tumoral immunity, primary tumor growth retardation and metastases in a murine model of lung cancer. METHODS: Grouped C57BL/6 and congenic B cell deficient mice (B(−/−)) bearing footpad 3LL tumors were treated with PBS, TLR9 agonist, control oligonucelotide, RT or the combination of RT and TLR9 agonist. Immune phenotype of splenocytes and serum IFN-γ and IL-10 levels were analyzed by FACS and ELISA, 24 h after treatment. Tumor growth, lung metastases and survival rate were monitored and tumor specific antibodies in serum and deposition in tumor tissue were measured by ELISA and immunofluorescence. RESULTS: TLR9 agonist expanded and activated B cells and plasmacytoid dendritic cells in wild-type mice and natural killer DCs (NKDCs) in B cell-deficient (B(−/−)) mice bearing ectopic Lewis lung adenocarcinoma (3LL). Combined RT with TLR9 agonist treatment inhibited 3LL tumor growth in both wild type and B(−/−) mice. A strong tumor-specific humoral immune response (titer: 1/3200) with deposition of mouse IgG auto-antibodies in tumor tissue were found in wildtype mice, whereas the number of tumor infiltrating NKDCs increased in B(−/−) mice following RT+ TLR9 agonist therapy. Furthermore, mice receiving combination therapy had fewer lung metastases and a higher survival than single treatment cohorts. CONCLUSIONS: Combination therapy with TLR9 agonist and RT induces systemic anti-tumoral humoral response, augments tumoral infiltration of NKDCs, reduces pulmonary metastases and improves survival in a murine model of 3LL cancer. |
format | Online Article Text |
id | pubmed-3364192 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33641922012-06-04 An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy Zhang, Huagang Liu, Laibin Yu, Dong Kandimalla, Ekambar R. Sun, Hui Bin Agrawal, Sudhir Guha, Chandan PLoS One Research Article PURPOSE: Recent studies have shown that a new generation of synthetic agonist of Toll-like receptor (TLR) 9 consisting a 3′-3′-attached structure and a dCp7-deaza-dG dinucultodie shows more potent immunostimulatory effects in both mouse and human than conventional CpG oligonucleotides. Radiation therapy (RT) provides a source of tumor antigens that are released from dying, irradiated, tumor cells without causing systemic immunosuppression. We, therefore, examined effect of combining RT with a designer synthetic agonist of TLR9 on anti-tumoral immunity, primary tumor growth retardation and metastases in a murine model of lung cancer. METHODS: Grouped C57BL/6 and congenic B cell deficient mice (B(−/−)) bearing footpad 3LL tumors were treated with PBS, TLR9 agonist, control oligonucelotide, RT or the combination of RT and TLR9 agonist. Immune phenotype of splenocytes and serum IFN-γ and IL-10 levels were analyzed by FACS and ELISA, 24 h after treatment. Tumor growth, lung metastases and survival rate were monitored and tumor specific antibodies in serum and deposition in tumor tissue were measured by ELISA and immunofluorescence. RESULTS: TLR9 agonist expanded and activated B cells and plasmacytoid dendritic cells in wild-type mice and natural killer DCs (NKDCs) in B cell-deficient (B(−/−)) mice bearing ectopic Lewis lung adenocarcinoma (3LL). Combined RT with TLR9 agonist treatment inhibited 3LL tumor growth in both wild type and B(−/−) mice. A strong tumor-specific humoral immune response (titer: 1/3200) with deposition of mouse IgG auto-antibodies in tumor tissue were found in wildtype mice, whereas the number of tumor infiltrating NKDCs increased in B(−/−) mice following RT+ TLR9 agonist therapy. Furthermore, mice receiving combination therapy had fewer lung metastases and a higher survival than single treatment cohorts. CONCLUSIONS: Combination therapy with TLR9 agonist and RT induces systemic anti-tumoral humoral response, augments tumoral infiltration of NKDCs, reduces pulmonary metastases and improves survival in a murine model of 3LL cancer. Public Library of Science 2012-05-30 /pmc/articles/PMC3364192/ /pubmed/22666458 http://dx.doi.org/10.1371/journal.pone.0038111 Text en Zhang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Zhang, Huagang Liu, Laibin Yu, Dong Kandimalla, Ekambar R. Sun, Hui Bin Agrawal, Sudhir Guha, Chandan An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy |
title | An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy |
title_full | An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy |
title_fullStr | An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy |
title_full_unstemmed | An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy |
title_short | An In Situ Autologous Tumor Vaccination with Combined Radiation Therapy and TLR9 Agonist Therapy |
title_sort | in situ autologous tumor vaccination with combined radiation therapy and tlr9 agonist therapy |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364192/ https://www.ncbi.nlm.nih.gov/pubmed/22666458 http://dx.doi.org/10.1371/journal.pone.0038111 |
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