Photodynamic immune stimulation eradicates primary pigmented melanoma and induces long-lasting anti-tumor immunity

Background: Melanoma is highly aggressive with limited options in advanced disease. Photodynamic therapy (PDT) has shown poor efficacy in pigmented melanoma due to restricted light penetration and intrinsic ROS resistance. A novel approach is investigated here. Methods: Full-thickness (4 mm) S91 pigmented melanoma grown intradermally in syngeneic immunocompetent (DBA) mice was treated using dual photosensitizers targeting tumor cells and microvasculature, together with a topical optical clearing agent. Anti-tumor immune effects were investigated in multiple functional assays, and the mechanisms-of-action were explored. Results: Primary tumor was eradicated in all mice, with 95% disease-free survival at 90 d, falling to 20% upon CD8 + T-cell depletion pre-treatment. The median survival in nude mice was 21 d. Treated DBA mice also rejected systemic tumor re-challenge at 30 d post treatment. There was delayed growth of untreated contralateral tumors and of tumors co-injected into naïve mice together with splenocytes from treated mice. Biomarker analysis showed rapid tumor infiltration by CD8+ and CD3+ T cells, reduced suppressive myeloid populations, and widespread immune activation. Gene expression profiling revealed enrichment of immune-related pathways and long-lasting memory. Conclusions: Photodynamic immune stimulation treatment can destroy primary pigmented melanoma far beyond the depth of light penetration and has potent anti-tumor systemic efficacy.