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

Ling Cai,David S Shames,Adeeb Alomar,Jane E Johnson,Benjamin J Drapkin ,Wei Zou,Ralph J Deberardinis,Gaoxiang Jia,Jun Chen,Junya Fujimoto,Victor Stastny,Chendong Yang,Luc Girard,Karine Pozo,Ignacio I Wistuba,John D Minna,Yang Xie,Christin S Kuo,Esra A Akbay,Mahboubeh Papari-Zareei,Dhruba Deb,Yongwen Li,Lin Yang,Fang Huang,Guanghua Xiao,Kenneth E Huffman ,Hongyu Liu,Tao Wang,Yu An Zhang ,Adi F Gazdar

doi:10.1038/s42003-021-01842-7

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 may help guide the design of treatment regimens in SCLC.

Highlights

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
We found that while expression of ASCL1 and NEUROD1 seems to be mutually exclusive in cell lines, they seem to co-express in many of the tumor samples; a small set of samples with low NE scores still express ASCL1 or NEUROD1; in “George_2015”, “Jiang_2016” and our own data set, we have observed rare POU2F3+ samples that have high NE scores
As classic SCLC is driven by lineage factor ASCL1 whereas variant SCLC with loss of NE genes is driven by YAP1, we examine the functional roles of YAP1 and ASCL1 in regulating the interferon-stimulated genes (ISGs) in SCLC cell lines

Summary

Introduction

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. Thirty-five years ago, it was observed that by contrast to classic SCLC cell lines (which grew in tissue culture as floating cell aggregates), a subset of patient-derived SCLC lines behaved differently—growing as adherent monolayers in culture, with morphologically larger cells, more prominent nucleoli, and expressed few or no NE markers[15,16]. These characteristics led such tumors to be termed “variant” or “non-NE” SCLC. We investigated the immune phenotypes associated with variable NE scores in SCLC and other cancer types

Methods

Results

Conclusion