Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater T cell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation. [Display omitted] •Most small cell lung cancer (SCLC) tumors share a small PLCG2-high subpopulation•This PLCG2-high SCLC subpopulation is linked to metastasis and poor prognosis•SCLC is enriched in profibrotic and immunosuppressive monocytes/macrophages•The presence of myeloid cells is associated with the PLCG2-high SCLC subpopulation Chan et al. use single-cell transcriptome sequencing and imaging techniques to study the heterogeneity and tumor microenvironment of clinical small cell lung cancer specimens. This analysis identifies a PLCG2-high-expressing subpopulation linked to metastasis and poor prognosis, and an enrichment of a monocyte/macrophage population with a profibrotic, immunosuppressive phenotype.