2019年4月1日
Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer.
The Journal of experimental medicine
- 巻
- 216
- 号
- 4
- 開始ページ
- 982
- 終了ページ
- 1000
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1084/jem.20180870
Immune checkpoint blockade against programmed cell death 1 (PD-1) and its ligand PD-L1 often induces durable tumor responses in various cancers, including non-small cell lung cancer (NSCLC). However, therapeutic resistance is increasingly observed, and the mechanisms underlying anti-PD-L1 (aPD-L1) antibody treatment have not been clarified yet. Here, we identified two unique secreted PD-L1 splicing variants, which lacked the transmembrane domain, from aPD-L1-resistant NSCLC patients. These secreted PD-L1 variants worked as "decoys" of aPD-L1 antibody in the HLA-matched coculture system of iPSC-derived CD8 T cells and cancer cells. Importantly, mixing only 1% MC38 cells with secreted PD-L1 variants and 99% of cells that expressed wild-type PD-L1 induced resistance to PD-L1 blockade in the MC38 syngeneic xenograft model. Moreover, anti-PD-1 (aPD-1) antibody treatment overcame the resistance mediated by the secreted PD-L1 variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1 variants.
- リンク情報
- ID情報
-
- DOI : 10.1084/jem.20180870
- PubMed ID : 30872362
- PubMed Central 記事ID : PMC6446862