TY - JOUR
T1 - Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer
AU - Gong, Bo
AU - Kiyotani, Kazuma
AU - Sakata, Seiji
AU - Nagano, Seiji
AU - Kumehara, Shun
AU - Baba, Satoko
AU - Besse, Benjamin
AU - Yanagitani, Noriko
AU - Friboulet, Luc
AU - Nishio, Makoto
AU - Takeuchi, Kengo
AU - Kawamoto, Hiroshi
AU - Fujita, Naoya
AU - Katayama, Ryohei
N1 - Publisher Copyright:
© 2019 Gong et al.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85064226778&partnerID=8YFLogxK
U2 - 10.1084/jem.20180870
DO - 10.1084/jem.20180870
M3 - Article
C2 - 30872362
AN - SCOPUS:85064226778
SN - 0022-1007
VL - 216
SP - 982
EP - 1000
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -