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Immunosuppressive effects of interleukin-12 coexpression in melanoma antigen gene–modified dendritic cell vaccines

Cancer Gene Therapy volume 9, pages 875–883 (2002)Cite this article

Abstract

Genetic immunotherapy with tumor antigen gene–modified dendritic cells (DC) generates robust immunity, although antitumor protection is not complete in all models. Previous experience in a model in which C57BL/6 mice immunized with DC transduced with adenoviral vectors expressing MART-1 demonstrated a 20–40% complete protection to a tumor challenge with B16 melanoma cells. Tumors that did develop in immunized mice had slower growth kinetics compared to tumors implanted in naïve mice. In the present study, we wished to determine if the supraphysiological production of the Th1-skewing cytokine interleukin-12 (IL-12) could enhance immune activation and antitumor protection in this model. In a series of experiments immunizing mice with DC cotransduced with MART-1 and IL-12, antitumor protection and antigen-specific splenocyte cytotoxicity and interferon γ production inversely correlated with the amount of IL-12 produced by DC. This adverse effect of IL-12 could not be explained by a direct cytotoxic effect of natural killer cells directed towards DC, nor the production of nitric oxide leading to down-regulation of the immune response — the two mechanisms previously recognized to explain immune-suppressive effects of IL-12–based vaccine therapy. In conclusion, in this animal model, IL-12 production by gene-modified DC leads to a cytokine-induced dose-dependent inhibition of antigen-specific antitumor protection.

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Acknowledgements

This work was supported, in part, by NIH/NCI Grants RO1 CA77623, RO1 CA79976, T32 CA75956, and K12 CA76905 (all to JSE), the Stacy and Evelyn Kesselman Research Fund, and the Monkarsh Fund. AR is a recipient of an American Society of Clinical Oncology Career Development Award and K23 CA93376.

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Authors and Affiliations

  1. Department of Surgery, University of California at Los Angeles, Los Angeles, 90095-1782, California, USA

    Antoni Ribas, Saral N Amarnani, Lisa H Butterfield, Vivian B Dissette & James S Economou

  2. Department of Medicine, University of California at Los Angeles, Los Angeles, 90095-1782, California, USA

    Antoni Ribas & John A Glaspy

  3. Department of Molecular and Medical Pharmacology, University of California at Los Angeles, Los Angeles, 90095-1782, California, USA

    Georgette M Buga & Louis J Ignarro

  4. Department of Experimental Radiation Oncology, University of California at Los Angeles, Los Angeles, 90095-1782, California, USA

    William H McBride

  5. Department of Microbiology, Immunology and Molecular Genetics, University of California at Los Angeles, Los Angeles, 90095-1782, California, USA

    James S Economou

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Correspondence to James S Economou.

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Ribas, A., Amarnani, S., Buga, G. et al. Immunosuppressive effects of interleukin-12 coexpression in melanoma antigen gene–modified dendritic cell vaccines. Cancer Gene Ther 9, 875–883 (2002). https://doi.org/10.1038/sj.cgt.7700512

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