Data from Topical Resiquimod Elicits Systemic Protection and Improves Anti–PD-1 Therapy in Melanoma via Priming of CD8+ T Cells

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Abstract The Toll-like receptor (TLR) 7/8 agonist resiquimod shows promise for treating cutaneous T-cell lymphoma and actinic keratosis, yet its mechanism of action remains unclear. We demonstrated that topical resiquimod significantly inhibited melanoma growth across various genetic and syngeneic mouse models, prolonged survival, and reduced lymph node metastasis in vivo. Resiquimod suppressed B16 melanoma growth, with an effect superior to that of imiquimod. The therapeutic effect was CD8+ T cell–dependent, as evidenced by the loss of efficacy upon CD8+ T-cell depletion or in Rag2−/− mice. Resiquimod increased intratumoral CD45+ inflammatory cells, particularly antigen-experienced PD-1+CD62L−CD8+ effector T cells, and enhanced their Ki-67 and granzyme B expression. Resiquimod significantly expanded Pmel- and Trp2-specific CD8+ T cells in the presence of dendritic cells (DC). Topical treatment of melanoma-bearing mice induced systemic protection in rechallenge experiments. In addition, combining topical resiquimod with anti–PD-1 antibodies led to superior inhibition of tumor growth and metastasis across multiple melanoma models. Proteomic analysis revealed increased granzyme B and CD26 and decreased phosphorylated FOXO3a after treatment. In patient-derived organoids and melanoma slice cultures, resiquimod induced significant tumor killing and CD8+ T-cell activation, further augmented by PD-1 antibodies. Our findings support the conclusion that resiquimod promotes CD8+ T-cell priming via DCs and enhances the therapeutic efficacy of anti–PD-1 checkpoint blockade in melanoma.

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