Oral communication, iL38

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

Monobenzome increases the immunogenicity of melanoma cells, and is effective as melanoma immunotherapy

Based on its immunogenicity, immunotherapy of melanoma is extensively studied as a new type of treatment. Since treatment-related skin depigmentation is considered a favourable prognostic sign during melanoma intervention, we here aimed at the reverse approach of inducing vitiligo to achieve effective anti-melanoma immunity. The phenolic compound monobenzone induces progressive skin depigmentation that is clinically and histologically indistinguishable from vitiligo vulgaris. Here, we present a comprehensive study of how monobenzone increases the immunogenicity of melanoma cells, leading to anti-melanoma immunity and melanoma growth inhibition. We showed that monobenzone inactivates tyrosinase enzyme in melanoma cells, leading to decreased cellular melanin synthesis, as well as the formation of quinone metabolites that bind to cysteine residues in proteins, thereby forming quinone haptens to melanosomal proteins. Moreover, monobenzone-tyrosinase interaction induced increased levels of reactive oxygen species, and the release of tyrosinase- and MART-1-containing CD63+ exosomes from monobenzone-exposed melanoma cells. We also found that monobenzone induces ubiquitination of tyrosinase as well as melanosome autophagy; a lysosomal degradation process leading to the targeting of tyrosinase to MHC class-II compartments. Monobenzone-exposed melanoma cells activated human dendritic cells, thereby generating a signal for immune activation, leading to the activation of melanoma-reactive human CD8+ T cells, in contrast to unexposed melanoma cells. Together, these data show that monobenzone, by its specific effects on the enzyme tyrosinase, induces potent CD8+ T cell immunity against auto-antigens expressed by melanocytes and melanoma cells. Monobenzone induced a melanoma antigen-specific immune response in vivo, incorporating NK-, B- and T cells, which abolished subcutaneous B16.F10 melanoma growth in up to 85% of C57BL/6 mice, when combined with immune-stimulatory imiquimod cream and CpG oligodeoxynucleotide injections (MIC therapy). Importantly, this regimen induced over 100 days of tumor-free survival in up to 60% of the mice, and forcefully suppressed tumor growth upon re-challenge after MIC treatment cessation. Based on these results, we have started a clinical trial in melanoma patients.

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