Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, 510140, China.
NMPA Key Laboratory for Safety Evaluation of Cosmetics, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China.
Adv Sci (Weinh). 2023 Dec;10(36):e2303753. doi: 10.1002/advs.202303753. Epub 2023 Nov 22.
The increased use of low-dose computed tomography screening has led to more frequent detection of early stage lung tumors, including minimally invasive adenocarcinoma (MIA). To unravel the intricacies of tumor cells and the immune microenvironment in MIA, this study performs a comprehensive single-cell transcriptomic analysis and profiles the transcriptomes of 156,447 cells from fresh paired MIA and invasive adenocarcinoma (IA) tumor samples, peripheral blood mononuclear cells, and adjacent normal tissue samples from three patients with synchronous multiple primary lung adenocarcinoma. This study highlights a connection and heterogeneity between the tumor ecosystem of MIA and IA. MIA tumor cells exhibited high expression of aquaporin-1 and angiotensin II receptor type 2 and a basal-like molecular character. Furthermore, it identifies that cathepsin B tumor-associated macrophages may over-activate CD8 T cells in MIA, leading to an enrichment of granzyme K senescent CD8 T cells, indicating the possibility of malignant progression behind the indolent appearance of MIA. These findings are further validated in 34 MIA and 35 IA samples by multiplexed immunofluorescence. These findings provide valuable insights into the mechanisms that maintain the indolent nature and prompt tumor progression of MIA and can be used to develop more effective therapeutic targets and strategies for MIA patients.
低剂量计算机断层扫描筛查的广泛应用导致了更多早期肺癌肿瘤的检出，包括微浸润性腺癌（MIA）。为了揭示 MIA 肿瘤细胞和免疫微环境的复杂性，本研究进行了全面的单细胞转录组分析，并对 3 例同步多原发肺腺癌患者的新鲜配对 MIA 和浸润性腺癌（IA）肿瘤样本、外周血单核细胞和相邻正常组织样本中的 156,447 个细胞的转录组进行了分析。本研究强调了 MIA 和 IA 肿瘤生态系统之间的联系和异质性。MIA 肿瘤细胞高表达水通道蛋白-1 和血管紧张素 II 受体 2，具有基底样分子特征。此外，本研究还发现组织蛋白酶 B 肿瘤相关巨噬细胞可能在 MIA 中过度激活 CD8 T 细胞，导致 granzyme K 衰老 CD8 T 细胞的富集，表明 MIA 惰性外观背后存在恶性进展的可能性。这些发现通过多重免疫荧光在 34 例 MIA 和 35 例 IA 样本中得到了进一步验证。这些发现为维持 MIA 惰性和促进肿瘤进展的机制提供了有价值的见解，并可用于为 MIA 患者开发更有效的治疗靶点和策略。
