Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200240, China.
J Transl Med. 2023 Jun 20;21(1):400. doi: 10.1186/s12967-023-04257-6.
Upregulation of the PD-L1 (CD274) immune checkpoint ligand on the tumor surface facilitates tumor immune escape and limits the application of immunotherapy in various cancers, including breast cancer. However, the mechanisms underlying high PD-L1 levels in cancers are still poorly understood.
Bioinformatics analyses and in vivo and in vitro experiments were carried out to assess the association between CD8 T lymphocytes and TIMELESS (TIM) expression, and to discover the mechanisms of TIM, the transcription factor c-Myc, and PD-L1 in breast cancer cell lines.
The circadian gene TIM enhanced PD-L1 transcription and facilitated the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Bioinformatic analyses of our RNA sequencing data in TIM-knockdown breast cancer cells and public transcriptomic datasets showed that TIM might play an immunosuppressive role in breast cancer. We found that TIM expression was inversely associated with CD8 T lymphocyte infiltration in human breast cancer samples and subcutaneous tumor tissues. In vivo and in vitro experiments demonstrated that TIM knockdown increased CD8 T lymphocyte antitumor activity. Furthermore, our results showed that TIM interacts with c-Myc to enhance the transcriptional capability of PD-L1 and facilitates the aggressiveness and progression of breast cancer through the intrinsic and extrinsic roles of PD-L1 overexpression. Moreover, public database analysis suggested that high TIM levels were positively related to PD-L1 inhibitor therapeutic response.
Mechanistically, we first found that TIM could upregulate PD-L1 by interacting with c-Myc to enhance the transcriptional capability of c-Myc to PD-L1. Altogether, our findings not only provide a novel therapeutic strategy to treat breast cancer by targeting the oncogenic effect of TIM but also indicate that TIM is a promising biomarker for predicting the benefit of anti-PD-L1 immunotherapy.
肿瘤表面 PD-L1（CD274）免疫检查点配体的上调促进了肿瘤免疫逃逸，并限制了免疫疗法在包括乳腺癌在内的各种癌症中的应用。然而，癌症中 PD-L1 水平升高的机制仍知之甚少。
进行了生物信息学分析以及体内和体外实验，以评估 CD8 T 淋巴细胞与 TIMESLESS（TIM）表达之间的关联，并发现 TIM、转录因子 c-Myc 和乳腺癌细胞系中 PD-L1 的机制。
昼夜节律基因 TIM 通过 PD-L1 过表达的内在和外在作用增强 PD-L1 转录，促进乳腺癌的侵袭性和进展。在 TIM 敲低的乳腺癌细胞和公共转录组数据集的我们的 RNA 测序数据的生物信息学分析中，TIM 可能在乳腺癌中发挥免疫抑制作用。我们发现 TIM 表达与人类乳腺癌样本和皮下肿瘤组织中 CD8 T 淋巴细胞浸润呈负相关。体内和体外实验表明，TIM 敲低增加了 CD8 T 淋巴细胞的抗肿瘤活性。此外，我们的结果表明，TIM 与 c-Myc 相互作用，增强 PD-L1 的转录能力，并通过 PD-L1 过表达的内在和外在作用促进乳腺癌的侵袭性和进展。此外，公共数据库分析表明，高 TIM 水平与 PD-L1 抑制剂治疗反应呈正相关。
从机制上讲，我们首次发现 TIM 可以通过与 c-Myc 相互作用上调 PD-L1，从而增强 c-Myc 对 PD-L1 的转录能力。总之，我们的研究结果不仅为通过靶向 TIM 的致癌作用治疗乳腺癌提供了一种新的治疗策略，而且表明 TIM 是预测抗 PD-L1 免疫治疗获益的有前途的生物标志物。
