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

Joji Nagasaki, Takashi Inozume, Nicolas Sax, Ryo Ariyasu, Masakazu Ishikawa, Kazuo Yamashita, Masahito Kawazu, Toshihide Ueno, Takuma Irie, Etsuko Tanji, Takao Morinaga, Akiko Honobe, Takehiro Ohnuma, Mitsuru Yoshino, Takekazu Iwata, Katsushige Kawase, Keita Sasaki, Toyoyuki Hanazawa, Vitaly Kochin, Tatsuyoshi KawamuraHiroyuki Matsue, Masayuki Hino, Hiroyuki Mano, Yutaka Suzuki, Hiroyoshi Nishikawa, Yosuke Togashi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number110331
JournalCell Reports
Volume38
Issue number5
DOIs
Publication statusPublished - Feb 1 2022
Externally publishedYes

Keywords

  • exhausted T cell
  • neoantigen
  • PD-1 blockade therapy
  • single-cell RNA sequencing
  • single-cell TCR sequencing
  • tumor microenvironment
  • tumor-draining lymph node
  • tumor-specific T cell

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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