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Dendritic cell therapy with interferon-α synergistically suppresses outgrowth of established tumors in a murine colorectal cancer model

Gene Therapy volume 13, pages 78–87 (2006)Cite this article

Abstract

Both dendritic cell (DC)-based immunotherapy and interferon (IFN)-α therapy have been proved to have potent long-lasting antitumor effects. In anticipation of synergistic antitumor effects, we performed combination therapy with DCs and IFN-α gene-transduced murine colorectal cancer MC38 cells (MC38-IFN-α). DCs incubated with MC38-IFN-α, but not neomycin-resistance gene-transduced MC38 cells (MC38-Neo), effectively enhanced proliferation of allogeneic splenocytes in vitro. In 12 of 17 mice, DCs in combination with MC38-IFN-α prevented the development of a parental tumor, while DCs and MC38-Neo did in only three of 17 mice (P=0.008). In a therapeutic model of an established parental tumor, inoculation of DCs and MC38-IFN-α suppressed the growth of the established parental tumors significantly compared with the administration of DCs with MC38-Neo or naive splenocytes with MC38-IFN-α (P=0.016 and 0.024, respectively). Analyses of immunohistochemistry and tumor-infiltrating mononuclear cells showed that CD8+, CD11c+, and NK1.1+ cells markedly infiltrated the established tumors of mice treated with DCs and MC38-IFN-α. From the results of observation of parental tumor outgrowth in immune cell-depleted mice, CD8+ cells, and asialo-GM-1+ cells were thought to contribute to the antitumor effects induced by the combination therapy. Furthermore, MC38-specific cytolysis was detected when splenocytes of mice inoculated with DCs and MC38-IFN-α cells were stimulated with MC38-IFN-α cells in vitro. Since DC-based immunotherapy in combination with IFN-α-expressing tumor cells induces potent antitumor cellular immune responses, it should be considered for clinical application.

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Abbreviations

DC:

dendritic cell

IFN:

interferon

MC38-IFN-α:

IFN-α-overexpressing MC38

MC38-Neo:

neomycin-resistance gene-transduced MC38

MC38-WT:

MC38 wild type

MHC:

major histocompatibility complex

CTL:

cytotoxic T-lymphocytes

IL:

interleukin

B6:

C57BL/6

CM:

complete medium

ELISA:

enzyme-linked immunosorbent assay

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling assay

ATCC:

American Type Culture Collection

HBSS:

Hank's balanced salt solution

FITC:

fluorescein isothiocyanate

OCT:

optimal clotting temperature

E:T:

effector to target ratio.

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Acknowledgements

This study was supported in part by a grant from Grant-in-Aid for Scientific Research (C) from The Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Second Department of Internal Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan

    S Ishii, K Hiroishi, J Eguchi, A Hiraide & M Imawari

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  1. S Ishii
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  3. J Eguchi
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Correspondence to K Hiroishi.

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Ishii, S., Hiroishi, K., Eguchi, J. et al. Dendritic cell therapy with interferon-α synergistically suppresses outgrowth of established tumors in a murine colorectal cancer model. Gene Ther 13, 78–87 (2006). https://doi.org/10.1038/sj.gt.3302608

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