PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted Tcell clonotypes.

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

doi:10.1016/j.celrep.2022.110331

Abstract

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating Tcells that directly attack tumor cells (tumor-specific Tcells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander Tcells. Here, using single-cell sequencing, we show that TILs include skewed Tcell 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 Tcell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such Tex clonotypes, mainly from TDLNs.

Highlights

The gain of immune escape mechanism(s), including increases in the expression of various immunosuppressive molecules, such as PD-1/PD-1 ligands, is an important process during cancer development and progression (Schreiber et al, 2011; Topalian et al, 2015; Zou et al, 2016)
PD-1 blockade superresponders have a considerable population of skewed Tex clonotypes in the tumor microenvironment (TME) First, we used both droplet-based 50 scRNA-seq and scTCR-seq to analyze four tumor-infiltrating T cell samples from three melanoma patients who received PD-1 blockade therapy
tumor-infiltrating lymphocytes (TILs) from sitematched tumors were collected before PD-1 blockade therapy (MEL02-1) and after treatment (MEL02-2) (Figure S1)

Summary

Introduction

The gain of immune escape mechanism(s), including increases in the expression of various immunosuppressive molecules, such as PD-1/PD-1 ligands, is an important process during cancer development and progression (Schreiber et al, 2011; Topalian et al, 2015; Zou et al, 2016).

Results

Discussion

Conclusion