Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer

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.

Small 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.