Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 216, Issue 4, Pages 982-1000Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20180870
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Funding
- Ministry of Education, Culture, Sports, Science and Technology/Japan Society for the Promotion of Science KAKENHI [JP17H06327, JP16H04715, JP17K07205]
- Japan Agency for Medical Research and Development [JP18cm0106203h0003, JP18ck0106231h0003, JP18ck0106364h0002]
- European Research Council starting grant [717034]
- Vehicle Racing Commemorative Foundation
- TAKEDA
- Toppan printing
- Fujifilm
- TAIHO Pharmaceutical
- AstraZeneca
- Boehringer-Ingelheim
- Bristol-Myers Squibb
- Inivata
- Lilly
- Loxo
- OncoMed
- Onxeo
- Pfizer
- Roche-Genentech
- Sanofi-Aventis
- Servier
- OSE Pharma
- European Research Council (ERC) [717034] Funding Source: European Research Council (ERC)
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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-L1variants. Collectively, our results elucidated a novel resistant mechanism of PD-L1 blockade antibody mediated by secreted PD-L1variants.
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