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Immunotargeting and eradication of orthotopic melanoma using a chemokine-enhanced DNA vaccine

Gene Therapy volume 20, pages 939–948 (2013)Cite this article

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Abstract

DNA vaccines are attractive candidates for tumor immunotherapy. However, the potential of DNA vaccines in treating established malignant lesions has yet to be demonstrated. Here we demonstrate that transient alteration of either intratumoral or intradermal (ID) chemotactic gradients provide a favorable milieu for DNA vaccine-mediated activation of tumor-specific immune response in both prophylactic and therapeutic settings. Specifically, we show that priming of established B16 ID melanoma lesions via forced intratumoral expression of CCL21 boosted DNA vaccination-dependent systemic cytotoxic immune response leading to the regression of tumor nodules. In this setting, application of CCL20 was not effective likely due to the engagement of the regulatory T cells. However, priming of the skin at DNA vaccine administration sites outside the tumor bed with both CCL20 and CCL21 chemokines along with structural modifications of the DNA vaccine significantly improved vaccine efficacy. This optimized ID vaccination regimen led to the inhibition of distant established melanomas and prolonged tumor-free survival of mice observed in 60% of vaccinated animals with complete tumor remission in 30%. These effects were mediated by extranodal priming and activation of T cells at vaccine administration sites and progressive accumulation of systemic antigen-specific cytotoxic T cells (CTLs) on successive vaccinations. These results underscore the potential of chemokine-enhanced DNA vaccination to mount therapeutic immune response against established tumors.

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Acknowledgements

We thank Drs T Sato, S Waldman and L Eisenlohr for helpful discussions. This research was supported in part by: Thomas Jefferson University pilot grant, Melanoma Research Foundation grant, and Pennsylvania Department of Health grant SAP# 4100051723 to VA and the Commonwealth of Pennsylvania through the American College of Radiology and the Radiation Therapy Oncology Group to UR. Jefferson Medical College Dean’s Research Program provided support for DMK, ML, MF and JL.

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Authors and Affiliations

  1. Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    O Igoucheva, D M Kemp, M Larijani, M Farber, J Lorton, U Rodeck & V Alexeev

  2. Department of Dermatology, University of Florence, Firenze, Italy

    M Grazzini

  3. Temple University School of Medicine, Philadelphia, PA, USA

    A Pidich

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  1. O Igoucheva
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Correspondence to V Alexeev.

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Igoucheva, O., Grazzini, M., Pidich, A. et al. Immunotargeting and eradication of orthotopic melanoma using a chemokine-enhanced DNA vaccine. Gene Ther 20, 939–948 (2013). https://doi.org/10.1038/gt.2013.17

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