High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer

• Published in: Cancer cell 2022-12, Vol.40 (12), p.1503-1520.e8
• Main Authors: Salcher, Stefan, Sturm, Gregor, Horvath, Lena, Untergasser, Gerold, Kuempers, Christiane, Fotakis, Georgios, Panizzolo, Elisa, Martowicz, Agnieszka, Trebo, Manuel, Pall, Georg, Gamerith, Gabriele, Sykora, Martina, Augustin, Florian, Schmitz, Katja, Finotello, Francesca, Rieder, Dietmar, Perner, Sven, Sopper, Sieghart, Wolf, Dominik, Pircher, Andreas, Trajanoski, Zlatko
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; cell-cell communication; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Neutrophils - metabolism; patient stratification; single-cell sequencing; therapy response; tissue-resident neutrophils; Tumor Microenvironment
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2022.10.008

Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity with diverse immune cell infiltration patterns, which has been linked to therapy sensitivity and resistance. However, full understanding of how immune cell phenotypes vary across different patient subgroups is lacking. Here, we dissect the NSCLC tumor microenvironment at high resolution by integrating 1,283,972 single cells from 556 samples and 318 patients across 29 datasets, including our dataset capturing cells with low mRNA content. We stratify patients into immune-deserted, B cell, T cell, and myeloid cell subtypes. Using bulk samples with genomic and clinical information, we identify cellular components associated with tumor histology and genotypes. We then focus on the analysis of tissue-resident neutrophils (TRNs) and uncover distinct subpopulations that acquire new functional properties in the tissue microenvironment, providing evidence for the plasticity of TRNs. Finally, we show that a TRN-derived gene signature is associated with anti-programmed cell death ligand 1 (PD-L1) treatment failure. [Display omitted] •High-resolution single-cell atlas of the tumor microenvironment (TME) in NSCLC•Histological tumor subtypes and driver genes imprint specific cellular TME patterns•In-depth characterization of tissue-resident neutrophil (TRN) subpopulations•TRN gene signature identifies patients refractory to treatment with PD-L1 inhibitor Salcher et al. integrate non-small cell lung cancer (NSCLC) single-cell datasets, refine patient stratification, and reveal histological and genotypic associations with tumor microenvironment (TME) composition. Single-cell sequencing of cells with low mRNA content identifies tissue-resident neutrophil (TRN) subpopulations with non-canonical functional properties. TRN gene signature is associated with immune-checkpoint inhibitor treatment failure.