Details

Autor(en) / Beteiligte

• Miao, Yu Rebecca
• Thakkar, Kaushik N
• Qian, Jin
• Kariolis, Mihalis S
• Huang, Wei
• Nandagopal, Saravanan
• Yang, Teddy Tat Chi
• Diep, Anh N
• Cherf, Gerald Maxwell
• Xu, Yu
• Moon, Eui Jung
• Xiao, Yiren
• Alemany, Haizea
• Li, Tiane
• Yu, Wenhua
• Wei, Bo
• Rankin, Erinn B
• Giaccia, Amato J

Titel

Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer

Ist Teil von

• Clinical cancer research, 2021-08, Vol.27 (15), p.4435-4448

Ort / Verlag

United States

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• Ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB), with reported low patient response rates. We found that the immune checkpoint ligand PD-L2 is robustly expressed in patient samples of ovarian cancers and other malignancies exhibiting suboptimal response to ICB but not in cancers that are ICB sensitive. Therefore, we hypothesize that PD-L2 can facilitate immune escape from ICB through incomplete blockade of the PD-1 signaling pathway. We engineered a soluble form of the PD-1 receptor (sPD-1) capable of binding and neutralizing both PD-L2 and PD-L1 with ×200 and ×10,000 folds improvement in binding affinity over wild-type PD-1 leading to superior inhibition of ligand-mediated PD-1 activities. Both and analyses performed in this study demonstrated that the high-affinity sPD-1 molecule is superior at blocking both PD-L1- and PD-L2-mediated immune evasion and reducing tumor growth in immune-competent murine models of ovarian cancer. The data presented in this study provide justification for using a dual targeting, high-affinity sPD-1 receptor as an alternative to PD-1 or PD-L1 therapeutic antibodies for achieving superior therapeutic efficacy in cancers expressing both PD-L2 and PD-L1.