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

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

PROVIDER: PRJNA1142945 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30090426_1.fastq.gz	Fastqsanger.gz
	SRR30090426_2.fastq.gz	Fastqsanger.gz
	SRR30090427_1.fastq.gz	Fastqsanger.gz
	SRR30090427_2.fastq.gz	Fastqsanger.gz

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

Project description:Melanoma is one of the most commonly diagnosed malignancies and serves as a model for studying immunotherapy. The B16 melanoma model is characterized by low T cell infiltration in the tumor, and blocking the PD-1 pathway shows no significant anti-tumor activity, mirroring melanoma patients with a cold tumor immunophenotype. 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 Tyr knockout B16 melanoma cells using CRISPR/Cas9 and discovered that tyrosinase in melanoma significantly inhibits the anti-tumor activity of T cells. Tyrosinase deficiency significantly increases T-cell infiltration and 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 Tregs in PD-1 knockout mice. Targeting tyrosinase may enhance the anti-tumor efficacy of PD-1 blockade in cold tumors, offering a novel strategy to render cold tumors responsive to immunotherapy. Clinically, higher levels of tyrosinase expression in human melanoma are associated with a poorer prognosis, indicating that our findings could potentially improve the efficacy of immunotherapy in melanoma patients.

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