Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma

Abstract

Recent developments in immuno-oncology demonstrate that not only cancer cells, but also features of the tumor microenvironment guide precision medicine. Still, the relationship between tumor and microenvironment remains poorly understood. To overcome this limitation and identify clinically relevant microenvironmental and cancer features, we applied single-cell RNA sequencing to lung adenocarcinomas. While the highly heterogeneous carcinoma cell transcriptomes reflected histological grade and activity of relevant oncogenic pathways, our analysis revealed two distinct microenvironmental patterns. We identified a prognostically unfavorable group of tumors with a microenvironment composed of cancer-associated myofibroblasts, exhausted CD8+ T cells, proinflammatory monocyte-derived macrophages and plasmacytoid dendritic cells (CEP2 pattern) and a prognostically favorable group characterized by myeloid dendritic cells, anti-inflammatory monocyte-derived macrophages, normal-like myofibroblasts, NK cells and conventional T cells (MAN2C pattern). Our results show that single-cell gene expression profiling allows to identify patient subgroups based on the tumor microenvironment beyond cancer cell-centric profiling.

The single-cell transcriptional landscape of lung carcinoid tumors

“…Beyond CD8+ T cells, myeloid cells in the microenvironment can modulate the response to immune checkpoint inhibitors [33]. Across all three lung carcinoids analyzed, we observed a consistent decrease in tissue-resident alveolar macrophages and an increase in monocyte-derived myeloid cells, compared to normal lung tissue, which has likewise been observed in lung adenocarcinomas [10, 14]. Monocyte-derived myeloid cells can give rise to monocyte-derived dendritic cells or monocyte-derived macrophages exhibiting different functionalities in the tumor microenvironment [20].…”

“…Tissue samples were enzymatically dissociated and subjected to singlecell RNA sequencing using a commercial droplet-based system. Single-cell gene expression data of 7 normal lung tissue samples from a previously published cohort (patients 4-10) [14] were included in the subsequent analyses. Altogether, we analyzed 73,105 single-cell transcriptomes of which 64,697 high-quality transcriptomes remained after quality control and filtering (Fig.…”

“…Fig. 5A-B) [14]. Together, the lymphoid microenvironment of lung carcinoids resembles the lymphoid cell compartment of normal lung parenchyma.…”

“…Fig. 5A, C) [14]. The highest proportion of pericytes was found in case 1 which was diagnosed as a typical carcinoid whereas fewer pericytes were found in patients 2 and 3 diagnosed with atypical carcinoids (Fig.…”

“…Moreover, predicting the efficacy of modern targeted and immune therapies is limited by intratumoral heterogeneity, where tumors may harbor primary resistant tumor cell subclones, as well as the complex tumor microenvironment, modulating immune responses against the tumor. Single-cell gene expression profiling allows to overcome this limitation and has already provided valuable insights into the cellular heterogeneity of lung adenocarcinomas [10–14].…”