The study investigates the role of pre-existing CD8 T-cells in the response to PD-1 blockade therapy in patients with metastatic melanoma. Using quantitative immunohistochemistry, multiplex immunofluorescence, and next-generation sequencing, the researchers found that CD8 T-cell density at the invasive margin and within tumors was significantly higher in patients who responded to treatment with pembrolizumab compared to those who progressed. Patients with higher CD8, PD-1, and PD-L1 expression at the invasive margin and inside tumors showed better clinical outcomes. The proximity of PD-1 and PD-L1-expressing cells was also associated with response to therapy. Additionally, a more restricted T-cell receptor (TCR) repertoire, indicating clonal expansion, was correlated with clinical response. A predictive model based on CD8 density at the invasive margin was validated in an independent cohort, accurately predicting responses in 9 out of 15 patients. These findings suggest that the presence and activation of pre-existing CD8 T-cells, regulated by PD-1/PD-L1 interactions, are crucial for the efficacy of PD-1 blockade therapy.The study investigates the role of pre-existing CD8 T-cells in the response to PD-1 blockade therapy in patients with metastatic melanoma. Using quantitative immunohistochemistry, multiplex immunofluorescence, and next-generation sequencing, the researchers found that CD8 T-cell density at the invasive margin and within tumors was significantly higher in patients who responded to treatment with pembrolizumab compared to those who progressed. Patients with higher CD8, PD-1, and PD-L1 expression at the invasive margin and inside tumors showed better clinical outcomes. The proximity of PD-1 and PD-L1-expressing cells was also associated with response to therapy. Additionally, a more restricted T-cell receptor (TCR) repertoire, indicating clonal expansion, was correlated with clinical response. A predictive model based on CD8 density at the invasive margin was validated in an independent cohort, accurately predicting responses in 9 out of 15 patients. These findings suggest that the presence and activation of pre-existing CD8 T-cells, regulated by PD-1/PD-L1 interactions, are crucial for the efficacy of PD-1 blockade therapy.