PD-1 Blockade Therapy Promotes Novel Infiltration of Tumor-Specific T-Cell Clonotypes

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (Tex) or nonexhaustion signatures (Tnon-ex), using single-cell sequencing. Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster responded to autologous tumor cell lines. After PD-1 blockade, new tumor-specific clonotypes in the Tex cluster appeared in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote novel infiltration of tumor-specific T-cell clonotypes, mainly from TDLNs.