Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer

Bo Gong, Kazuma Kiyotani, Seiji Sakata, Seiji Nagano, Shun Kumehara, Satoko Baba, Benjamin Besse, Noriko Yanagitani, Luc Friboulet, Makoto Nishio, Kengo Takeuchi, Hiroshi Kawamoto, Naoya Fujita, Ryohei Katayama

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)982-1000
Number of pages19
JournalJournal of Experimental Medicine
Volume216
Issue number4
DOIs
Publication statusPublished - 01-04-2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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