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Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT

Abstract

To establish a more efficient treatment for immunotherapy against solid tumors, we have evaluated the antitumor effect by coexpression of a chemokine CCL21/secondary lymphoid tissue chemokine and a costimulatory molecule LIGHT in colon carcinoma C26. C26 cells expressing either CCL21 or LIGHT exhibited a significantly reduced tumor growth in vivo, and mice inoculated with these cells showed a prolonged survival, but eventually all these mice died. In contrast, C26 cells expressing both CCL21 and LIGHT exhibited a minimal tumor growth in vivo, and all these mice survived healthily with a tumor remission and consequently acquired a strong protective immunity. A markedly increased infiltration of mature dendritic cells (DCs), and CD8+ T cells was observed in the tumor mass, and their spleen cells showed a greatly enhanced cytotoxic T lymphocyte (CTL) activity against C26 tumor and interferon (IFN)-γ production. Neutralization of IFN-γ or depletion of CD8+ or CD4+ T cells significantly reduced the antitumor activity. These results suggest that the combined treatment with CCL21 and LIGHT is able to induce a synergistic antitumor effect to eradicate tumor completely by greatly enhancing tumor-infiltration of lymphocytes including mature DCs and CD8+ T cells, resulting in markedly augmented CTL activity and IFN-γ production.

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Abbreviations

DC:

dendritic cell

SLC:

secondary lymphoid tissue chemokine

APC:

antigen-presenting cell

Th:

T helper cell

CTL:

cytotoxic T lymphocyte

RT:

reverse transcriptase

IRES:

internal ribosome entry site

ATCC:

American Type Culture Collection

mAb:

monoclonal antibody

C26-CCL21:

C26 cells transfected with pcDNA3.1-CCL21 cDNA

C26-LIGHT:

C26 cells transfected with pcDNA3.1-LIGHT cDNA

C26-C+L:

C26 cells transfected with pcDNA3.1-LIGHT cDNA/IRES/CCL21 cDNA

C26-Vector:

C26 cells transfected with pcDNA3.1 vector alone

CD40L:

CD40 ligand

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Acknowledgements

We thank Drs T Kitamura and E Takada for kindly providing pMX-IRES/EGFP and technical help, respectively.

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Correspondence to Takayuki Yoshimoto.

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Supported by a Grant-in-Aid for Scientific Research on Priority Areas and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

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Hisada, M., Yoshimoto, T., Kamiya, S. et al. Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT. Cancer Gene Ther 11, 280–288 (2004). https://doi.org/10.1038/sj.cgt.7700676

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