Department of Biochemistry, College of Life Science & Biotechnology, and.
Brain Korea 21 (BK21) PLUS Program, Initiative for Biological Functions & Systems, Yonsei University, Seoul, Republic of Korea.
JCI Insight. 2020 Jul 23;5(14):128633. doi: 10.1172/jci.insight.128633.
Expression of immune checkpoint ligands (ICLs) is necessary to trigger the inhibitory signal via immune checkpoint receptors (ICRs) in exhausted T cells under tumor immune microenvironment. Nevertheless,to our knowledge, ICL expression profile in cancer patients has not been investigated. Using previously reported RNA-seq data sets, we found that expression of ICLs was patient specific but their coexpression can be patterned in non-small-cell lung cancers (NSCLCs). Since the expression of PD-L1 and poliovirus receptor (PVR) among various ICLs was independently regulated, we could stratify the patients who were treated with anti-PD-1 later into 4 groups according to the expression level of PD-L1 and PVR. Of interest, high PVR and low PVR expressions in PD-L1-expressing patients enriched nonresponders and responders to PD-1 blockade, respectively, helping in further selection of responders. Using a genetically engineered cancer model, we also found that PVR-deficient and PD-L1-sufficient tumor-bearing mice were highly sensitive to anti-PD-1 therapy, whereas PVR-sufficient and PD-L1-deficient tumor-bearing mice were resistant to anti-PD-1 therapy. Taken together, our study provides a concept that combinatorial expression patterns of PVR and PD-L1 are key determinants for PD-1 blockade and furthermore suggest a better therapeutic usage of immune checkpoint blockades (ICBs).
免疫检查点配体（ICLs）的表达对于在肿瘤免疫微环境下耗尽的 T 细胞通过免疫检查点受体（ICRs）触发抑制信号是必要的。然而，据我们所知，尚未研究癌症患者中 ICL 的表达谱。使用先前报道的 RNA-seq 数据集，我们发现 ICL 的表达是患者特异性的，但它们的共表达可以在非小细胞肺癌（NSCLCs）中形成模式。由于各种 ICL 中 PD-L1 和脊髓灰质炎病毒受体（PVR）的表达独立调控，我们可以根据 PD-L1 和 PVR 的表达水平将接受抗 PD-1 治疗的患者分为 4 组。有趣的是，在 PD-L1 表达的患者中，高 PVR 和低 PVR 表达分别富集了对 PD-1 阻断的无反应者和有反应者，有助于进一步选择有反应者。使用基因工程癌症模型，我们还发现 PVR 缺陷和 PD-L1 充足的荷瘤小鼠对抗 PD-1 治疗高度敏感，而 PVR 充足和 PD-L1 缺陷的荷瘤小鼠对抗 PD-1 治疗具有抗性。总之，我们的研究提供了一个概念，即 PVR 和 PD-L1 的组合表达模式是 PD-1 阻断的关键决定因素，并进一步提示免疫检查点阻断（ICBs）的更好治疗用途。
