An in situ autologous tumor vaccination with combined radiation therapy and TLR9 agonist therapy

Huagang Zhang, Laibin Liu, Dong Yu, Ekambar R. Kandimalla, Hui (Herb) Sun, Sudhir Agrawal, Chandan Guha

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere38111
JournalPLoS One
Volume7
Issue number5
DOIs
StatePublished - May 30 2012

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Radiotherapy
radiotherapy
agonists
Tumors
Vaccination
vaccination
therapeutics
neoplasms
mice
Neoplasms
metastasis
Bearings (structural)
Neoplasm Metastasis
Neoplasm Antibodies
Cells
lungs
B-Lymphocytes
Therapeutics
B-lymphocytes
Lung

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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 (Herb); Agrawal, Sudhir; Guha, Chandan.

In: PLoS One, Vol. 7, No. 5, e38111, 30.05.2012.

Research output: Contribution to journalArticle

Zhang, Huagang ; Liu, Laibin ; Yu, Dong ; Kandimalla, Ekambar R. ; Sun, Hui (Herb) ; Agrawal, Sudhir ; Guha, Chandan. / An in situ autologous tumor vaccination with combined radiation therapy and TLR9 agonist therapy. In: PLoS One. 2012 ; Vol. 7, No. 5.
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abstract = "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.",
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AU - Zhang, Huagang

AU - Liu, Laibin

AU - Yu, Dong

AU - Kandimalla, Ekambar R.

AU - Sun, Hui (Herb)

AU - Agrawal, Sudhir

AU - Guha, Chandan

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