Melanoma protective antitumor immunity activated by catalytic DNA

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Melanoma incidence is rising globally, with current therapies like BRAF/MEK inhibitors and immune checkpoint antibodies facing treatment resistance.
• Alternative therapeutic strategies are crucial for managing melanoma, especially given the limitations of existing treatments.
• DNAzymes represent a promising class of therapeutic agents, with early clinical trials indicating efficacy and a favorable safety profile.

Purpose of the Study:

• To investigate the expression of c-Jun in human primary and metastatic melanoma.
• To explore the role of T cell immunity in DNAzyme-mediated inhibition of melanoma growth.
• To assess the potential of DNAzymes to prevent tumor growth in non-treated sites and subsequent new tumors.

Main Methods:

• Analysis of c-Jun expression in human melanoma and benign nevi samples.
• Treatment of B16F10 melanoma-bearing mice with Dz13, a DNAzyme targeting c-Jun/AP-1.
• Evaluation of tumor growth, abscopal effects, and adaptive immunity using anti-CD4/anti-CD8 antibodies.
• Assessment of cleaved caspase-3 levels, intratumoral vascularity, and immune cell infiltration.

Main Results:

• c-Jun was highly expressed in melanoma cells (80% primary, 83% metastatic) but minimally in benign melanocytes (11%).
• Dz13 suppressed growth of both treated and untreated melanomas, demonstrating an abscopal effect dependent on CD4+/CD8+ T cells.
• Dz13 treatment led to increased cleaved caspase-3, reduced tumor vascularity, and enhanced CD4+ T cell infiltration, with established protective immunity against new tumor formation.

Conclusions:

• This study demonstrates the first abscopal effect of a DNAzyme on tumor growth.
• Dz13 treatment establishes protective immunity, preventing the growth of subsequent tumors in the same animal.
• Dz13 holds potential as a therapeutic agent for melanoma, possibly preventing relapse through adaptive immunity.