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Updated: Nov 5, 2025
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology
Published on: May 2, 2025
Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer
Yu Rebecca Miao1, Kaushik N Thakkar1, Jin Qian1,2
1Department of Radiation Oncology, Stanford School of Medicine, Stanford, California.
Purpose:
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.
Experimental Design:
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.
Results:
Both in vitro and in vivo 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.
Conclusions:
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.
Insights
This study identifies PD-L2 as a key factor in ovarian cancer's resistance to immune checkpoint blockade (ICB). A novel soluble PD-1 (sPD-1) molecule effectively blocks PD-L1 and PD-L2, enhancing anti-tumor immunity.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Ovarian cancer shows limited response to immune checkpoint blockade (ICB).
- Immune checkpoint ligand PD-L2 is highly expressed in ICB-resistant cancers.
- PD-L2 may contribute to immune escape by incompletely blocking PD-1 signaling.
Purpose of the Study:
- To investigate the role of PD-L2 in ICB resistance in ovarian cancer.
- To develop a novel therapeutic agent targeting both PD-L1 and PD-L2.
Main Methods:
- Engineered a high-affinity soluble PD-1 (sPD-1) receptor.
- Tested sPD-1's binding affinity and inhibitory activity against PD-L1 and PD-L2.
- Evaluated sPD-1 efficacy in vitro and in vivo using murine ovarian cancer models.
Main Results:
- Engineered sPD-1 demonstrated significantly improved binding affinity for PD-L1 and PD-L2 compared to wild-type PD-1.
- sPD-1 effectively inhibited PD-L1- and PD-L2-mediated immune evasion in vitro and in vivo.
- Treatment with sPD-1 reduced tumor growth in murine ovarian cancer models.
Conclusions:
- High-affinity sPD-1 is a potent inhibitor of PD-L1 and PD-L2 signaling.
- sPD-1 shows therapeutic potential for ovarian cancers expressing both PD-L1 and PD-L2.
- Dual targeting of PD-L1 and PD-L2 with sPD-1 offers a promising alternative to current ICB therapies.
