Author:
Cai Ling,Liu Hongyu,Huang Fang,Fujimoto Junya,Girard Luc,Chen Jun,Li Yongwen,Zhang Yuan,Deb Dhruba,Stastny Victor,Kuo Christin S.,Jia Gaoxiang,Yang Chendong,Zou Wei,Alomar Adeeb,Huffman Kenneth,Papari-Zareei Mahboubeh,Yang Lin,Drapkin Benjamin,Akbay Esra,Shames David S.,Wistuba Ignacio I.,Wang Tao,Xiao Guanghua,DeBerardinis Ralph J.,Minna John D.,Xie Yang,Gazdar Adi F.
Abstract
ABSTRACTSmall cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed “variant” due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings provide a new framework to guide design of treatment regimens in SCLC.
Publisher
Cold Spring Harbor Laboratory