Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer
| العنوان: | Neutralization of PD-L2 is Essential for Overcoming Immune Checkpoint Blockade Resistance in Ovarian Cancer |
|---|---|
| المؤلفون: | Teddy Tat Chi Yang, Tiane Li, Yu Rebecca Miao, Bo Wei, Anh N. Diep, Haizea Alemany, Eui Jung Moon, Wei Huang, Amato J. Giaccia, Mihalis Kariolis, Yu Xu, Saravanan Nandagopal, Kaushik N. Thakkar, Yiren Xiao, Jin Qian, Erinn B. Rankin, Gerald Maxwell Cherf, Wenhua Yu |
| المصدر: | Clin Cancer Res |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cancer Research, Article, Mice, Immune system, In vivo, medicine, Animals, Humans, Receptor, Immune Checkpoint Inhibitors, Ovarian Neoplasms, biology, business.industry, medicine.disease, Programmed Cell Death 1 Ligand 2 Protein, Immune checkpoint, Blockade, Oncology, Drug Resistance, Neoplasm, Cancer research, biology.protein, Female, Antibody, Signal transduction, Ovarian cancer, business |
| الوصف: | 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. |
| تدمد: | 1557-3265 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::60c8ef058f21bc083507078bf8ce4b47 https://pubmed.ncbi.nlm.nih.gov/34011561 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....60c8ef058f21bc083507078bf8ce4b47 |
| قاعدة البيانات: | OpenAIRE |
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