Cell-autonomous immune gene expression is repressed in pulmonary neuroendocrine cells and small cell lung cancer

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.