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Background <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月15日

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  • Rong Huang,
  • Yingbin Wang,
  • Haitao Teng,
  • Mengjun Xu,
  • Kexin He,
  • Yingzhuo Shen,
  • Guo Guo,
  • Xinyu Feng,
  • Tianhan Li,
  • Binhui Zhou,
  • Marc Bajenoff,
  • Toby Lawrence,
  • Yinming Liang,
  • Liaoxun Lu,
  • Lichen Zhang

摘要

Background

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.

Results

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.

Conclusions

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.