Single-Cell Transcriptome Identifies Drug-Resistance Signature and Immunosuppressive Microenvironment in Metastatic Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is a deadly neuroendocrine malignancy with high metastasis. However, the heterogeneity of metastatic SCLC at the single-cell level remains elusive. The single-cell transcriptome of a total of 24 081 cells in metastatic lymph node samples from seven SCLC patients via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is examined. Genomic alterations are also examined by whole exome sequencing (WES) and the immune infiltration between SCLC and non-SCLC (NSCLC) is compared using public single-cell RNA sequencing (scRNA-seq) data. It is identified that malignant cells in lymph-node metastatic SCLC have inter-patient and intra-tumor heterogeneity characterized by distinct and expression patterns. High expression of genes such as in WNT pathway is associated with drug resistance in malignant cells. Compared to NSCLC, SCLC harbors a unique immunosuppressive tumor microenvironment. Malignant cells exhibit a pattern of attenuated MHC-I antigen presentation-related gene expression, which is associated with relatively low proportion of exhausted T cells. Natural killer (NK) cells display impaired antitumor function with high expression of . This work characterizes the inter-patient and intra-tumor heterogeneity of metastatic SCLC and uncovers the exhaustion signatures in NK cells, which may pave the way for novel treatments for SCLC including immune checkpoint blockade-based immunotherapy.