Single-cell and spatial transcriptomics analysis of non-small cell lung cancer

TLDR

Lung cancer is the second most common cancer and leading cause of cancer death worldwide, and its tumor microenvironment contains diverse immune cells, especially myeloid cells that promote disease progression. The study profiled approximately 900,000 cells from 25 treatment‑naïve adenocarcinoma and squamous‑cell carcinoma patients using single‑cell and spatial transcriptomics. The analysis revealed that anti‑inflammatory macrophages inversely correlate with NK/T cells and reduce NK cytotoxicity, that adenocarcinoma and squamous‑cell carcinoma share similar immune cell composition yet differ in checkpoint inhibitor co‑expression, and that macrophages undergo transcriptional reprogramming toward cholesterol export and a foetal‑like signature promoting iron efflux, providing a high‑resolution map of tumor‑associated macrophages.

Abstract

Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. Tumour ecosystems feature diverse immune cell types. Myeloid cells, in particular, are prevalent and have a well-established role in promoting the disease. In our study, we profile approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma by single-cell and spatial transcriptomics. We note an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, and with reduced NK cell cytotoxicity within the tumour. While we observe a similar cell type composition in both adenocarcinoma and squamous-cell carcinoma, we detect significant differences in the co-expression of various immune checkpoint inhibitors. Moreover, we reveal evidence of a transcriptional “reprogramming” of macrophages in tumours, shifting them towards cholesterol export and adopting a foetal-like transcriptional signature which promotes iron efflux. Our multi-omic resource offers a high-resolution molecular map of tumour-associated macrophages, enhancing our understanding of their role within the tumour microenvironment.