PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted 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, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (T ex) or nonexhaustion signatures (T non-ex). Among skewed clonotypes, those in the T ex , but not those in the T non-ex , cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the T ex cluster appear 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 infiltration of such T ex clonotypes, mainly from TDLNs. [Display omitted] • The tumor microenvironment has both skewed T ex and T non-ex clonotypes • Among skewed clonotypes, T ex , but not T non-ex , directly attack tumor cells • PD-1 blockade promotes T ex clonotype infiltration • TDLNs can be the origin of such T ex clonotypes Nagasaki et al. demonstrate that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype (T ex) directly attack tumor cells. PD-1 blockade therapy can promote expansion of preexisting tumor-specific T ex clonotypes, and infiltration of non-preexisting T ex clonotypes, mainly from tumor-draining lymph nodes. [ABSTRACT FROM AUTHOR]