PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes

Cell Rep. 2022 Feb 1;38(5):110331. doi: 10.1016/j.celrep.2022.110331.


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 (Tex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the Tex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the Tex 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 Tex clonotypes, mainly from TDLNs.

Keywords: PD-1 blockade therapy; exhausted T cell; neoantigen; single-cell RNA sequencing; single-cell TCR sequencing; tumor microenvironment; tumor-draining lymph node; tumor-specific T cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor / drug effects
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology*
  • Lymphocytes, Tumor-Infiltrating / drug effects*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Mice
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / metabolism
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology*


  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor