Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
J Natl Cancer Inst. 2023 Dec 6;115(12):1586-1596. doi: 10.1093/jnci/djad154.
Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer because outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that may contribute to the expression of these biomarkers remain incompletely uncovered.
We evaluated PD-L1 immunohistochemistry scores (SP142 and 28-8 assays) and TILs in our triple-negative breast cancer multiomics dataset and 2 immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression, and patient outcomes.
Despite TILs serving as a decent predictor for triple-negative breast cancer clinical outcomes, exceptions remained. Our study revealed that several genomic alterations were correlated with unexpected events. In particular, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified triple-negative breast cancers into 4 groups based on PD-L1 and TIL levels. The TIL-negative PD-L1-positive and TIL-positive PD-L1-negative groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL-positive PD-L1-positive tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-negative PD-L1-positive group, whereas GSK3B-induced degradation may cause undetectable PD-L1 expression in the TIL-positive PD-L1-negative group. These factors have the potential to affect the predictive function of both PD-L1 and TILs.
Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression, and prognosis in triple-negative breast cancer. Investigating and targeting these factors will advance precision immunotherapy for patients with this disease.
肿瘤浸润淋巴细胞（TILs）和程序性死亡受体 1 配体 1（PD-L1）在预测三阴性乳腺癌的临床结局方面仍然存在不足，因为这些生物标志物的表达与临床结局并不总是相关。可能导致这些生物标志物表达的基因组和转录组改变仍未完全发现。
我们评估了三阴性乳腺癌多组学数据集中和 2 项免疫治疗临床试验队列中 PD-L1 免疫组化评分（SP142 和 28-8 检测法）和 TILs。然后，我们分析了与 TILs、PD-L1 表达和患者结局相关的基因组和转录组改变。
尽管 TILs 是预测三阴性乳腺癌临床结局的良好指标，但仍存在例外。我们的研究表明，一些基因组改变与意外事件相关。特别是，PD-L1 表达可能导致某些患者中 TILs 与预后之间出现矛盾关系。因此，我们根据 PD-L1 和 TIL 水平将三阴性乳腺癌分为 4 组。TIL 阴性 PD-L1 阳性和 TIL 阳性 PD-L1 阴性组并非典型的“热”肿瘤；与 TIL 阳性 PD-L1 阳性肿瘤相比，这两组的预后均较差，免疫治疗效果也较低。PD-L1 的拷贝数变异和致癌信号激活与 TIL 阴性 PD-L1 阳性组的 PD-L1 表达相关，而 GSK3B 诱导的降解可能导致 TIL 阳性 PD-L1 阴性组中 PD-L1 表达不可检测。这些因素可能影响 PD-L1 和 TILs 的预测功能。
几种基因组和转录组改变可能导致三阴性乳腺癌中 TILs、PD-L1 表达和预后之间出现矛盾的影响。研究和靶向这些因素将推进该疾病患者的精准免疫治疗。
