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

• DOI: 10.1158/1078-0432.c.7059583
• Publication Date: 2024-02-05T14:00:23Z
• Authors: Yu Rebecca Miao; Kaushik N. Thakkar; Jin Qian; Mihalis S. Kariolis; Wei Huang; Saravanan Nandagopal; Teddy Tat Chi Yang; Anh N. Diep; Gerald Maxwell Cherf; Yu Xu; Eui Jung Moon; Yiren Xiao; Haizea Alemany; Tiane Li; Wenhua Yu; Bo Wei; Erinn B. Rankin; Amato J. Giaccia

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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.</p>Results:<p>Both <i>in vitro</i> and <i>in vivo</i> 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.</p>Conclusions:<p>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.</p></div>