Tyrosinase in melanoma inhibits anti-tumor activity of PD-1 deficient T cells.

Published in: BMC Biol 2025 May; 23(1): 135

Authors: Huang R, Wang Y, Teng H, Xu M, He K, Shen Y, Guo G, Feng X, Li T, Zhou B, Bajenoff M, Lawrence T, Liang Y, Lu L, Zhang L

Summary

Melanoma is one of the most commonly diagnosed malignancies and serves as a model for studying immunotherapy. The B16 melanoma model, resembling human cold tumors that lack T cell infiltration and show minimal response to PD-1 blockade, is widely used for studying melanoma and its resistance to immunotherapy. Therefore, understanding the molecular basis that prevents T cell-mediated anti-tumor activity in B16 melanoma is of great significance.In this study, we generated tyrosinase knockout B16 melanoma cells using CRISPR/Cas9 and discovered that tyrosinase in melanoma significantly inhibits the anti-tumor activity of T cells. Tyrosinase deficiency leads to a 3.80-fold increase in T-cell infiltration and enhances T-cell activation within the tumor. Single-cell RNA sequencing reveals an altered cold tumor immunophenotype in tyrosinase-deficient B16 melanoma. In wild-type mice, T cells in tyrosinase-deficient tumors express elevated levels of PD-1 and Foxp3. However, strikingly, in PD-1 deficient mice, the loss of tyrosinase in B16 melanoma unleashes the anti-tumor activity of PD-1 deficient T cells. This enhanced anti-tumor activity is explained by significantly increased tumor T cell infiltration accompanied by reduced frequencies of regulatory T cells in PD-1 knockout mice.These findings suggest that targeting tyrosinase could convert cold tumors into an immune-responsive state in vivo using murine models. Inhibiting tyrosinase could enhance the effectiveness of PD-1 blockade, offering a new approach for melanoma patients who fail in current PD-1 inhibitor treatment.

Link to Pubmed [PMID] – 40375241

Link to DOI – 10.1186/s12915-025-02237-4