Melanoma incidence is increasing worldwide, and although drugs such as BRAF/MEK small-molecule inhibitors and immune checkpoint antibodies improve patient outcomes, most patients ultimately fail these therapies and alternative treatment strategies are urgently needed. DNAzymes have recently undergone clinical trials with signs of efficacy and no serious adverse events attributable to the DNAzyme. Here we investigated c-Jun expression in human primary and metastatic melanoma. We also explored the role of T cell immunity in DNAzyme inhibition of primary melanoma growth and the prevention of growth in non-treated tumors after the cessation of treatment in a mouse model. c-Jun was expressed in 80% of melanoma cells in human primary melanomas (n = 17) and in 83% of metastatic melanoma cells (n = 38). In contrast, c-Jun was expressed in only 11% of melanocytes in benign nevi (n = 24). Dz13, a DNAzyme targeting c-Jun/AP-1, suppressed both Dz13-injected and untreated B16F10 melanoma growth in the same mice, an abscopal effect relieved in each case by administration of anti-CD4/anti-CD8 antibodies. Dz13 increased levels of cleaved caspase-3 within the tumors. New, untreated melanomas grew poorly in mice previously treated with Dz13. Administration of anti-CD4/anti-CD8 antibodies ablated this inhibitory effect and the tumors grew rapidly. Dz13 inhibited c-Jun expression, reduced intratumoral vascularity (vascular lumina area defined by CD31 staining), and increased CD4+ cells within the tumors. This study provides the first demonstration of an abscopal effect of a DNAzyme on tumor growth and shows that Dz13 treatment prevents growth of subsequent new tumors in the same animal. Dz13 may be useful clinically as a therapeutic antitumor agent by preventing tumor relapse through adaptive immunity.
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We thank Professor Mark J Smyth (Peter MacCallum Cancer Centre, Melbourne) for supply of antibodies, the Biomedical Imaging Facility, UNSW Mark Wainwright Analytical Centre for immunohistochemical staining, and Emeritus Professor Ian Dawes for critical review of the manuscript.
This study was supported by a Translational Program Grant from Cancer Institute of New South Wales, and Program and Fellowship support from National Health and Medical Research Council of Australia.
LMK designed, directed, and analyzed all aspects of this research; RAS and GMH directed and analyzed various elements in the study; CRP and BHC provided critical intellectual input; HC, E-AC, YL, JS, JE, TJD, PMF, and JSW performed the work and/or analyzed the data.
Conflict of interest
LMK has declared I.P. interests in Dz13. The remaining authors declare that they have no conflict of interest.
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Cai, H., Cho, E., Li, Y. et al. Melanoma protective antitumor immunity activated by catalytic DNA. Oncogene 37, 5115–5126 (2018). https://doi.org/10.1038/s41388-018-0306-0
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