Laboratory of Cancer Biology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, 210009, China.
Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Nanjing Medical University, Nanjing, 211166, China.
J Exp Clin Cancer Res. 2022 Feb 17;41(1):66. doi: 10.1186/s13046-022-02243-2.
The interaction between programmed death receptor (PD-1) and its ligand (PD-L1) is essential for suppressing activated T-lymphocytes. However, the precise mechanisms underlying PD-L1 overexpression in tumours have yet to be fully elucidated. Here, we describe that RelB participates in the immune evasion of prostate cancer (PCa) via cis/trans transcriptional upregulation of PD-L1.
Based on transcriptome results, RelB was manipulated in multiple human and murine PCa cell lines. Activated CD4 and CD8 T cells were cocultured with PCa cells with different levels of RelB to examine the effect of tumourous RelB on T cell immunity. Male mice were injected with murine PCa cells to validate the effect of RelB on the PD-1/PD-L1-mediated immune checkpoint using both tumour growth and metastatic experimental models.
PD-L1 is uniquely expressed at a high level in PCa with high constitutive RelB and correlates with the patients' Gleason scores. Indeed, a high level of PD-L1 is associated with RelB nuclear translocation in AR-negative aggressive PCa cells. Conversely, the silencing of RelB in advanced PCa cells resulted in reduced PD-L1 expression and enhanced susceptibility of PCa cells to the T cell immune response in vitro and in vivo. Mechanistically, a proximal NF-κB enhancer element was identified in the core promoter region of the human CD274 gene, which is responsible for RelB-mediated PD-L1 transcriptional activation. This finding provides an informative insight into immune checkpoint blockade by administering RelB within the tumour microenvironment.
This study deciphers the molecular mechanism by which tumourous RelB contributes to immune evasion by inhibiting T cell immunity via the amplification of the PD-L1/PD-1-mediated immune checkpoint.
程序性死亡受体（PD-1）与其配体（PD-L1）之间的相互作用对于抑制活化的 T 淋巴细胞至关重要。然而，肿瘤中 PD-L1 过表达的确切机制尚未完全阐明。在这里，我们描述了 RelB 通过顺式/反式转录上调 PD-L1 参与前列腺癌（PCa）的免疫逃逸。
基于转录组结果，在多种人源和鼠源 PCa 细胞系中操纵 RelB。用不同水平 RelB 的 PCa 细胞与活化的 CD4 和 CD8 T 细胞共培养，以检查肿瘤 RelB 对 T 细胞免疫的影响。雄性小鼠被注射鼠源 PCa 细胞，以使用肿瘤生长和转移实验模型验证 RelB 对 PD-1/PD-L1 介导免疫检查点的影响。
PD-L1 在具有高组成性 RelB 的 PCa 中独特地高表达，并与患者的 Gleason 评分相关。事实上，高水平的 PD-L1 与 AR 阴性侵袭性 PCa 细胞中 RelB 的核易位相关。相反，在晚期 PCa 细胞中沉默 RelB 导致 PD-L1 表达降低，并增强了 PCa 细胞对 T 细胞免疫反应的易感性，无论是在体外还是体内。从机制上讲，在人类 CD274 基因的核心启动子区域中鉴定出一个近端 NF-κB 增强子元件，该元件负责 RelB 介导的 PD-L1 转录激活。这一发现为在肿瘤微环境中通过给予 RelB 来阻断免疫检查点提供了有价值的见解。
本研究揭示了肿瘤 RelB 通过放大 PD-L1/PD-1 介导的免疫检查点来抑制 T 细胞免疫，从而促进免疫逃逸的分子机制。
