抗原特异性分析鉴定出与新辅助 PD-1 阻断治疗应答相关的 T-bet(+) 黑色素瘤特异性 CD8(+) T 细胞

Despite widespread immune profiling in cancer immunotherapy, the antigen-specific responses that drive clinical outcomes remain poorly defined. In a prospective neoadjuvant trial (NCT04013854) of a single-dose anti-PD-1 (nivolumab) in stage III melanoma, we performed antigen-specific profiling of melanoma and viral-specific CD8 + T cells across blood, tumor, and lymph node compartments. Using combinatorial tetramers, we detected melanoma-specific CD8 + T cells in 72% of HLA-A1, -A2, and -A3 patients.

These cells displayed distinct phenotypes shaped by tissue and antigen context. Tumor-infiltrating T-bet + intermediate exhausted CD8 + T cells were strongly associated with pathologic response, while CD39 + terminal exhausted cells marked non-response. T-bet and CD39 expression also stratified responses in uninvolved lymph nodes, suggesting early divergence of therapeutic immune trajectories. Longitudinal profiling revealed that circulating melanoma-specific CD8 + T cell dynamics was antigen-dependent and associated with clinical outcomes.

Our findings highlight the clinical value of antigen-specific profiling and identify mechanistic correlates of anti-PD-1 efficacy.