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

Cai, L.; Liu, H.; Huang, F.; Fujimoto, J.; Girard, L.; Chen, J.; Li, Y.; Zhang, Y.-a.; Deb, D.; Stastny, V.; Kuo, C. S.; Jia, G.; Yang, C.; Zou, W.; Aloma, A.; Huffman, K.; Papari-Zareei, M.; Yang, L.; Drapkin, B.; Akbay, E.; Shames, D. S.; Wistuba, I. I.; Wang, T.; Xiao, G.; DeBerardinis, R. J.; Minna, J. D.; Xie, Y.; Gazdar, A. F.

doi:10.1101/2020.07.28.225763

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bioRxiv · 10.1101/2020.07.28.225763

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

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Abstract

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.

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Cai, L., Liu, H., Huang, F., Fujimoto, J., Girard, L., Chen, J., Li, Y., Zhang, Y.-a., Deb, D., Stastny, V., Kuo, C. S., Jia, G., Yang, C., Zou, W., Aloma, A., Huffman, K., Papari-Zareei, M., Yang, L., Drapkin, B., Akbay, E., Shames, D. S., Wistuba, I. I., Wang, T., Xiao, G., DeBerardinis, R. J., Minna, J. D., Xie, Y., Gazdar, A. F.. 2020-07-29. Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer. https://doi.org/10.1101/2020.07.28.225763

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