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Novel and enhanced anti-melanoma DNA vaccine targeting the tyrosinase protein inhibits myeloid-derived suppressor cells and tumor growth in a syngeneic prophylactic and therapeutic murine model

Cancer Gene Therapy volume 21, pages 507–517 (2014)Cite this article

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Abstract

Melanoma is the most deadly type of skin cancer, constituting annually ∼75% of all cutaneous cancer-related deaths due to metastatic spread. Currently, because of metastatic spread, there are no effective treatment options for late-stage metastatic melanoma patients. Studies over the past two decades have provided insight into several complex molecular mechanisms as to how these malignancies evade immunological control, indicating the importance of immune escape or suppression for tumor survival. Thus, it is essential to develop innovative cancer strategies and address immune obstacles with the goal of generating more effective immunotherapies. One important area of study is to further elucidate the role and significance of myeloid-derived suppressor cells (MDSCs) in the maintenance of the tumor microenvironment. These cells possess a remarkable ability to suppress immune responses and, as such, facilitate tumor growth. Thus, MDSCs represent an important new target for preventing tumor progression and escape from immune control. In this study, we investigated the role of MDSCs in immune suppression of T cells in an antigen-specific B16 melanoma murine system utilizing a novel synthetic tyrosinase (Tyr) DNA vaccine therapy in both prophylactic and therapeutic models. This Tyr vaccine induced a robust and broad immune response, including directing CD8 T-cell infiltration into tumor sites. The vaccine also reduced the number of MDSCs in the tumor microenvironment through the downregulation of monocyte chemoattractant protein 1, interleukin-10, CXCL5 and arginase II, factors important for MDSC expansion. This novel synthetic DNA vaccine significantly reduced the melanoma tumor burden and increased survival in vivo, due likely, in part, to the facilitation of a change in the tumor microenvironment through MDSC suppression.

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Acknowledgements

We acknowledge members of the Weiner laboratory for significant contributions and/or critical reading and editing of the manuscript. DBW notes funding from the National Institutes of Health, Basser Research Center for BRCA and Inovio Pharmaceuticals. We also thank Penn CFAR and the ACC core facilities for their support.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    J Yan, C Tingey, R Lyde, T C Gorham, D K Choo, A Muthumani, D Myles, E L Reuschel, K Muthumani & D B Weiner

  2. Cherry Hill High School East, Cherry Hill, NJ, USA

    A Muthumani

  3. Department of Nutritional Sciences, Rutgers, The State University of New Jersey–New Brunswick, New Brunswick, NJ, USA

    L P Weiner

  4. Inovio Pharmaceutics, Blue Bell, PA, USA

    K A Kraynyak, J J Kim & N Y Sardesai

  5. Department of Pediatrics and Nemours Research Institute, Nemours Children’s Hospital, Orlando, FL, USA

    T H Finkel

  6. Department of Molecular Medicine and Center for Molecular Delivery, University of South Florida Morsani College of Medicine, Tampa, FL, USA

    K E Ugen

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Competing interests

DBW has grant funding, participates in industry collaborations and has received speaking honoraria and fees for consulting. This service includes serving on scientific review committees and advisory boards. Remuneration includes direct payments or stock or stock options and, in the interest of disclosure, therefore he notes potential conflicts associated with this work with Pfizer, Medimmune, Inovio, Merck, VGXi, OncoSec, Roche, Aldevron and possibly others. Licensing of technology from his laboratory has created over 100 jobs in the biotech/pharma industry. KEU also reports a conflict in terms of co-inventorship and stock ownership in technology licensed to Oncosec Medical Corporation. The other authors declare no conflict of interest. KAK, JJK and NYS are employees of Inovio Pharmaceuticals, and as such receive salary and benefits including ownership of stock and stock option from the company.

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Yan, J., Tingey, C., Lyde, R. et al. Novel and enhanced anti-melanoma DNA vaccine targeting the tyrosinase protein inhibits myeloid-derived suppressor cells and tumor growth in a syngeneic prophylactic and therapeutic murine model. Cancer Gene Ther 21, 507–517 (2014). https://doi.org/10.1038/cgt.2014.56

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