抑制 MYC 可抑制程序性细胞死亡配体 1 的表达，并增强三阴性乳腺癌的免疫治疗。
Inhibition of MYC suppresses programmed cell death ligand-1 expression and enhances immunotherapy in triple-negative breast cancer.
机构信息
Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Medical School of Nanjing University, Nanjing, Jiangsu 210093, China.
出版信息
Chin Med J (Engl). 2022 Oct 20;135(20):2436-2445. doi: 10.1097/CM9.0000000000002329.
BACKGROUND
Cancer immunotherapy has emerged as a promising strategy against triple-negative breast cancer (TNBC). One of the immunosuppressive pathways involves programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), but many patients derived little benefit from PD-1/PD-L1 checkpoint blockades treatment. Prior research has shown that MYC, a master transcription amplifier highly expressed in TNBC cells, can regulate the tumor immune microenvironment and constrain the efficacy of immunotherapy. This study aims to investigate the regulatory relationship between MYC and PD-L1, and whether a cyclin-dependent kinase (CDK) inhibitor that inhibits MYC expression in combination with anti-PD-L1 antibodies can enhance the response to immunotherapy.
METHODS
Public databases and TNBC tissue microarrays were used to study the correlation between MYC and PD-L1. The expression of MYC and PD-L1 in TNBCs was examined by quantitative real-time polymerase chain reaction and Western blotting. A patient-derived tumor xenograft (PDTX) model was used to evaluate the influence of a CDK7 inhibitor THZ1 on PD-L1 expression. Cell proliferation and migration were detected by 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation and cell migration assays. Tumor xenograft models were established for in vivo verification.
RESULTS
A high MYC expression level was associated with a poor prognosis and could alter the proportion of tumor-infiltrating immune cells (TIICs). The positive correlation between MYC and PD-L1 was confirmed by immunostaining samples from 165 TNBC patients. Suppression of MYC in TNBC caused a reduction in the levels of both PD-L1 messenger RNA and protein. In addition, antitumor immune response was enhanced in the TNBC cancer xenograft mouse model with suppression of MYC by CDK7 inhibitor THZ1.
CONCLUSIONS
The combined therapy of CDK7 inhibitor THZ1 and anti-PD-L1 antibody appeared to have a synergistic effect, which might offer new insight for enhancing immunotherapy in TNBC.
背景
癌症免疫疗法已成为治疗三阴性乳腺癌（TNBC）的一种有前途的策略。其中一种免疫抑制途径涉及程序性细胞死亡-1（PD-1）和程序性细胞死亡配体-1（PD-L1），但许多患者从 PD-1/PD-L1 检查点阻断治疗中获益甚少。先前的研究表明，高度表达于 TNBC 细胞中的主转录放大器 MYC 可以调节肿瘤免疫微环境并限制免疫疗法的疗效。本研究旨在研究 MYC 与 PD-L1 之间的调节关系，以及抑制 MYC 表达的细胞周期蛋白依赖性激酶（CDK）抑制剂与抗 PD-L1 抗体联合使用是否可以增强对免疫治疗的反应。
方法
使用公共数据库和 TNBC 组织微阵列研究 MYC 与 PD-L1 之间的相关性。通过定量实时聚合酶链反应和 Western blot 检测 TNBC 中 MYC 和 PD-L1 的表达。使用患者来源的肿瘤异种移植（PDTX）模型评估 CDK7 抑制剂 THZ1 对 PD-L1 表达的影响。通过 5-乙炔基-2'-脱氧尿苷（EdU）细胞增殖和细胞迁移测定检测细胞增殖和迁移。建立肿瘤异种移植模型进行体内验证。
结果
高 MYC 表达水平与不良预后相关，并可以改变肿瘤浸润免疫细胞（TIIC）的比例。通过对 165 例 TNBC 患者的免疫染色样本进行验证，证实了 MYC 与 PD-L1 之间的正相关关系。在 TNBC 中抑制 MYC 导致 PD-L1 信使 RNA 和蛋白水平降低。此外，通过 CDK7 抑制剂 THZ1 抑制 MYC，在 TNBC 癌症异种移植小鼠模型中增强了抗肿瘤免疫反应。
结论
CDK7 抑制剂 THZ1 和抗 PD-L1 抗体的联合治疗似乎具有协同作用，这可能为增强 TNBC 的免疫治疗提供新的思路。
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