State Key Laboratory of Molecular Oncology & Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
School of Life Sciences and Engineering, Handan University, Handan, Hebei Province, 056005, China.
Cell Biol Toxicol. 2024 Jul 23;40(1):56. doi: 10.1007/s10565-024-09892-3.
Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.
程序性细胞死亡配体 2（PD-L2）是程序性细胞死亡受体 1（PD-1）的配体，与它的同源配体 PD-L1 有 34%的同一性，并且与 PD-1 的结合亲和力高于 PD-L1。然而，PD-L2 在非小细胞肺癌（NSCLC）进展中的作用，特别是在烟草诱导的癌症进展中的作用，尚未完全阐明。在这里，我们发现 PD-L2 通过募集调节性 T 细胞（Tregs）促进了小鼠模型中的肿瘤生长。在 NSCLC 患者中，肿瘤样本中的 PD-L2 表达水平高于对照正常组织，并且与患者对抗 PD-1 治疗的反应呈正相关。机制上，PD-L2 在癌细胞上与其受体排斥性导向分子 B（RGMB）结合，激活细胞外信号调节激酶（Erk）和核因子 κB（NFκB），导致趋化因子 CCL20 的产生增加，从而招募 Tregs 并促进 NSCLC 进展。一致地，敲低 RGMB 或 NFκB p65 抑制了 PD-L2 诱导的 CCL20 产生，而沉默 PD-L2 抑制了 NSCLC 细胞对 Treg 的招募。此外，香烟烟雾和致癌剂苯并（a）芘（BaP）通过芳烃受体（AhR）介导的转录激活上调了肺上皮细胞中的 PD-L2，其缺失显著抑制了 BaP 诱导的 PD-L2 上调。这些结果表明，PD-L2 通过 RGMB/NFκB/CCL20 级联介导烟草诱导的 Treg 募集，靶向该途径可能在 NSCLC 中有治疗潜力。
