Journal
CANCER CELL
Volume 39, Issue 11, Pages 1479-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2021.09.008
Keywords
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Funding
- NCI [U2C CA233284, U54 CA209975, R01 CA197936, U24 CA213274, R35 CA263816, R01 CA217169, R01 CA240472]
- Robert J. and Helen C. Kleberg Foundation
- SU2C/VAI Epigenetics Dream Team
- Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center
- Druckenmiller Center for Lung Cancer Research
- AACR Lung Cancer Fellowship
- ASCO Young Investigator Award
- Parker Institute for Cancer Immunotherapy grant
- International Association for the Study of Lung Cancer grant
- NIH [K08 CA248723, K08 CA245206]
- NCI Cancer Center Support Grant [P30 CA08748]
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- Cycle for Survival
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The study reveals a greater tumor diversity in SCLC compared to lung adenocarcinoma, with a PLCG2-high SCLC phenotype showing stem-like, pro-metastatic features and predicting worse overall survival. Furthermore, SCLC demonstrates greater immune sequestration and less immune infiltration than lung adenocarcinoma.
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.
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