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.
Article
Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer
https://doi.org/10.21203/rs.3.rs-50416/v1
This work is licensed under a CC BY 4.0 License
Journal Publication
published 09 Mar, 2021
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small cell lung cancer
neuroendocrine
immune gene expression
lung cancer
Yes there is potential Competing Interest.
J.D.M. receives licensing fees from the NCI and UT Southwestern to distribute cell lines. R.J.D is on the advisory board for Agios Pharmaceuticals. D.S.S and W.Z. are currently employed by Genentech Inc. and own stock in Roche Holdings. I.I.W is speaker at Medscape, MSD, Genentech/Roche, PlatformQ Health, Pfizer, AstraZeneca, Merck; receives research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya; and is on the advisory boards for Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, and MSD.
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