Department of Clinical Trial, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310022, China.
Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.
Cell Death Dis. 2021 Jan 21;12(1):106. doi: 10.1038/s41419-021-03410-7.
Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor (p = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p < 0.001) but the worse outcomes in non-EGFR-treated (HR 2.623, p = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p = 0.001) and non-EGFR-treated patients (HR 0.308, p = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.
脑转移（BM）是肺癌的一种常见恶性事件。在这里，我们招募了 33 例肺癌脑寡转移患者，分别独立探索肺部和脑部的基因组特征和肿瘤免疫微环境（TIME）。进行基因组分析时，采用了靶向测序。我们发现，高频率的 ZFHX3 发生在肺部（40%）和脑部肿瘤（28%）中，这可能与脑转移事件有关；绝大多数患者在原发性肿瘤和 BM 中存在病变共享突变，证实了共同的克隆事件；并且 EGFR 是肺部和 BM 中最常出现的克隆基因，表明其具有驱动能力。为了描述 TIME 状态，我们还对 28 例配对样本的 T 细胞受体（TCR）库进行了测序，并对 CD8+肿瘤浸润淋巴细胞（TIL）和 PD-L1 表达进行了免疫组化（IHC）检测。通过比较，BM 的 TCR 克隆性高于肺部肿瘤，表明 BM 中存在更强的寡克隆 T 细胞扩增模式；原发性肿瘤的 TMB 高于寡转移 BM（13.9 对 8.7 突变，p=0.019）；BM 的 CD8+TIL 明显低于肺部肿瘤（10%对 30%，p=0.015），表明细胞毒性 T 细胞浸润水平较低；BM 与肺部肿瘤的 PD-L1 水平相当（p=0.722）。我们进一步研究了与脑手术后总生存期（OS）相关的潜在生物标志物。我们发现，较高的 TCR 克隆性与接受 EGFR 治疗的患者的 OS 延长相关（HR 0.175，p<0.001），但在未接受 EGFR 治疗的患者中则预后较差（HR 2.623，p=0.034）。更多的 CD8+TIL 是 EGFR 治疗（HR 0.160，p=0.001）和非 EGFR 治疗（HR 0.308，p=0.009）患者 OS 的独立阳性指标。这些发现为肺癌和脑寡转移提供了有意义的分子和临床认识。
