Department of Cardiothoracic Surgery, Zhongshan City People's Hospital, Zhongshan, P. R. China.
Geneseeq Research Institute, Nanjing Geneseeq Technology Inc, Nanjing, P. R. China.
Oncoimmunology. 2023 May 27;12(1):2215112. doi: 10.1080/2162402X.2023.2215112. eCollection 2023.
The evolution of immune profile from primary tumors to distant and local metastases in non-small cell lung cancer (NSCLC), as well as the impact of the immune background of primary tumors on metastatic potential, remains unclear. To address this, we performed whole-exome sequencing and immunohistochemistry for 73 paired primary and metastatic tumor samples from 41 NSCLC patients, and analyzed the change of immune profile from primary tumors to metastases and involved genetic factors. We found that distant metastases tended to have a decreased CD8+ T cell level along with an increased chromosomal instability (CIN) compared with primary tumors, which was partially ascribed to acquired DNA damage repair (DDR) deficiency. Distant metastases were characterized by immunosuppression (low CD8+ T cell level) and immune evasion (high PD-L1 level) whereas local metastases (pleura) were immune-competent with high CD8+ T cell, low CD4+ T cell and low PD-L1 level. Primary tumors with high levels of CD4+ T cells were associated with distant metastases rather than local metastases. Analysis of TCGA data and a single-cell RNA-sequencing dataset revealed a decreasing trend of major immune cells, such as CD8+ T cells, and an increasing trend of CD4 T helper cells (Th2 and Th1) in primary tumors with metastases from local to distant sites. Our study indicates that there are differences in the immune evolution between distant and local metastases, and that acquired DDR deficiency contributes to the immunosuppression in distant metastases of NSCLC. Moreover, the immune background of primary tumors may affect their metastatic potential.
非小细胞肺癌（NSCLC）原发肿瘤到远处和局部转移的免疫特征演变，以及原发肿瘤的免疫背景对转移潜能的影响尚不清楚。为了解决这个问题，我们对 41 名 NSCLC 患者的 73 对原发和转移肿瘤样本进行了全外显子测序和免疫组化分析，并分析了从原发肿瘤到转移瘤的免疫特征变化及其涉及的遗传因素。我们发现，与原发肿瘤相比，远处转移往往具有较低的 CD8+T 细胞水平和较高的染色体不稳定性（CIN），这部分归因于获得性 DNA 损伤修复（DDR）缺陷。远处转移表现为免疫抑制（低 CD8+T 细胞水平）和免疫逃逸（高 PD-L1 水平），而局部转移（胸膜）具有高 CD8+T 细胞、低 CD4+T 细胞和低 PD-L1 水平的免疫能力。高水平 CD4+T 细胞的原发肿瘤与远处转移而不是局部转移有关。对 TCGA 数据和单细胞 RNA 测序数据集的分析表明，在从局部到远处转移的原发肿瘤中，主要免疫细胞（如 CD8+T 细胞）呈下降趋势，而 CD4 辅助性 T 细胞（Th2 和 Th1）呈上升趋势。我们的研究表明，远处和局部转移之间的免疫演变存在差异，获得性 DDR 缺陷导致 NSCLC 远处转移的免疫抑制。此外，原发肿瘤的免疫背景可能影响其转移潜能。
