Single-Cell RNA Sequencing Unravels Distinct Tumor Microenvironment of Different Components of Lung Adenocarcinoma Featured as Mixed Ground-Glass Opacity

Abstract

Lung adenocarcinoma featured as mixed ground-glass opacity (mGGO) doubled its volume half of the time in comparison with that featured as pure ground-glass opacity (pGGO). The mechanisms underlying the heterogeneous appearance of mGGO remain elusive. In this study, we macro-dissected the solid (S) components and ground-glass (GG) components of mGGO and performed single-cell sequencing analyses of six paired components from three mGGO patients. A total of 19,391 single-cell profiles were taken into analysis, and the data of each patient were analyzed independently to obtain a common alteration. Cancer cells and macrophages were the dominant cell types in the S and GG components, respectively. Cancer cells in the S components, which showed relatively malignant phenotypes, were likely to originate from both the GG and S components and monitor the surrounding tumor microenvironment (TME) through an intricate cell interaction network. SPP1^hi macrophages were enriched in the S components and showed increased activity of chemoattraction, while macrophages in the GG components displayed an active antimicrobial process with a higher stress-induced state. In addition, the CD47-SIRPA axis was demonstrated to be critical in the maintenance of the GG components. Taken together, our study unraveled the alterations of cell components and transcriptomic features between different components in mGGOs.

Keywords: ground-glass opacity; intra-tumor heterogeneity; macrophage; non-small cell lung cancer; single-cell RNA sequencing.