Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12RΒ2 or IL-18Rα

I. K. Choi; J. S. Lee; S. N. Zhang; J. Park; K. M. Lee; C. H. Sonn; C. O. Yun

doi:10.1038/gt.2011.37

Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12RΒ₂ or IL-18Rα

I. K. Choi
, J. S. Lee
, S. N. Zhang
, J. Park
, K. M. Lee
, C. H. Sonn
, C. O. Yun

Department of New Biology

Research output: Contribution to journal › Article › peer-review

98 Scopus citations

Abstract

The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte-macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4 and CD8 T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12RΒ₂ or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.

Original language	English
Pages (from-to)	898-909
Number of pages	12
Journal	Gene Therapy
Volume	18
Issue number	9
DOIs	https://doi.org/10.1038/gt.2011.37
State	Published - Sep 2011

Bibliographical note

Funding Information:
This work was supported by grants from the Ministry of Knowledge Economy (10030051, Dr C-O Yun), the Korea Science and Engineering Foundation (R15-2004-024-02001-0, 2009K001644, 2010-0029220, Dr C-O Yun), the Korea Food and Drug Administration (KFDA-10172-332 to Dr C-O Yun), and Yonsei University College of Medicine faculty research grant (6-2010-0052, Dr C-O Yun). I-K Choi is a graduate student sponsored by KOSEF through National Core Research Center for Nanomedical Technology. J-S Lee and S-N Zhang are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.

Keywords

IL-12
IL-18
T cells expressing IL-12Rβ2 or IL-18Rα
cancer immunogene therapy
oncolytic adenovirus

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/gt.2011.37

Cite this

@article{25600760d4974dafbb8909b9e6a62286,

title = "Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12RΒ2 or IL-18Rα",

abstract = "The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte-macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4 and CD8 T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12RΒ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.",

keywords = "IL-12, IL-18, T cells expressing IL-12Rβ2 or IL-18Rα, cancer immunogene therapy, oncolytic adenovirus",

author = "Choi, \{I. K.\} and Lee, \{J. S.\} and Zhang, \{S. N.\} and J. Park and Lee, \{K. M.\} and Sonn, \{C. H.\} and Yun, \{C. O.\}",

note = "Funding Information: This work was supported by grants from the Ministry of Knowledge Economy (10030051, Dr C-O Yun), the Korea Science and Engineering Foundation (R15-2004-024-02001-0, 2009K001644, 2010-0029220, Dr C-O Yun), the Korea Food and Drug Administration (KFDA-10172-332 to Dr C-O Yun), and Yonsei University College of Medicine faculty research grant (6-2010-0052, Dr C-O Yun). I-K Choi is a graduate student sponsored by KOSEF through National Core Research Center for Nanomedical Technology. J-S Lee and S-N Zhang are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.",

year = "2011",

month = sep,

doi = "10.1038/gt.2011.37",

language = "English",

volume = "18",

pages = "898--909",

journal = "Gene Therapy",

issn = "0969-7128",

publisher = "Springer Nature",

number = "9",

}

TY - JOUR

T1 - Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12RΒ2 or IL-18Rα

AU - Choi, I. K.

AU - Lee, J. S.

AU - Zhang, S. N.

AU - Park, J.

AU - Lee, K. M.

AU - Sonn, C. H.

AU - Yun, C. O.

N1 - Funding Information: This work was supported by grants from the Ministry of Knowledge Economy (10030051, Dr C-O Yun), the Korea Science and Engineering Foundation (R15-2004-024-02001-0, 2009K001644, 2010-0029220, Dr C-O Yun), the Korea Food and Drug Administration (KFDA-10172-332 to Dr C-O Yun), and Yonsei University College of Medicine faculty research grant (6-2010-0052, Dr C-O Yun). I-K Choi is a graduate student sponsored by KOSEF through National Core Research Center for Nanomedical Technology. J-S Lee and S-N Zhang are graduate students sponsored by the Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea.

PY - 2011/9

Y1 - 2011/9

N2 - The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte-macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4 and CD8 T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12RΒ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.

AB - The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte-macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4 and CD8 T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12RΒ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.

KW - IL-12

KW - IL-18

KW - T cells expressing IL-12Rβ2 or IL-18Rα

KW - cancer immunogene therapy

KW - oncolytic adenovirus

UR - https://www.scopus.com/pages/publications/80052588142

U2 - 10.1038/gt.2011.37

DO - 10.1038/gt.2011.37

M3 - Article

C2 - 21451575

AN - SCOPUS:80052588142

SN - 0969-7128

VL - 18

SP - 898

EP - 909

JO - Gene Therapy

JF - Gene Therapy

IS - 9

ER -