Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.

Joseph M Chan,W Victoria Lai,Dig V.K Yarlagadda,Michael Offin,Tal Nawy,Metamia Ciampricotti,Charles M Rudin,James L Wang,Marina K Baine,Triparna Sen,David R Jones,Yubin Xie,Yanyun Li,Amber Bahr,Elisa De Stanchina,Andrew Chow,Thomas Walle,Ojasvi Chaudhary,John T Poirier,Viola Allaj,Travis J Hollmann,Besnik Qeriqi,Natasha Rekhtman,Ignas Masilionis,Fathema Uddin,Linas Mažutis ,Arvin Eric B Ruiz ,Vianne R Gao ,Dana Pe’er ,Umesh Bhanot ,Jacklynn V Egger ,Álvaro Quintanal-Villalonga ,Marissa S Mattar ,Matthew Bott

doi:10.1016/j.ccell.2021.09.008

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy that includes subtypes defined by differential expression of ASCL1, NEUROD1, and POU2F3 (SCLC-A, -N, and -P, respectively). To define the heterogeneity of tumors and their associated microenvironments across subtypes, we sequenced 155,098 transcriptomes from 21 human biospecimens, including 54,523 SCLC transcriptomes. We observe greater tumor diversity in SCLC than lung adenocarcinoma, driven by canonical, intermediate, and admixed subtypes. We discover a PLCG2-high SCLC phenotype with stem-like, pro-metastatic features that recurs across subtypes and predicts worse overall survival. SCLC exhibits greater immune sequestration and less immune infiltration than lung adenocarcinoma, and SCLC-N shows less immune infiltrate and greater Tcell dysfunction than SCLC-A. We identify a profibrotic, immunosuppressive monocyte/macrophage population in SCLC tumors that is particularly associated with the recurrent, PLCG2-high subpopulation.

Highlights

The prognosis for patients with small cell lung cancer (SCLC), the most aggressive lung cancer histology, remains exceptionally poor: most patients present with metastatic disease, and the recent addition of immune checkpoint blockade to firstline chemotherapy has only modestly improved median survival (Horn et al, 2018; Rudin et al, 2021)
In the midst of substantial heterogeneity, we identify a stem-like, pro-metastatic tumor subpopulation marked by high phospholipase C gamma 2 (PLCG2) expression that spans the full diversity of SCLC subtypes and predicts worse overall survival
We found that the fraction of combined cluster 6 cells out of all Mono/M4 cells is significantly higher in primary and metastatic SCLC samples compared with primary lung adenocarcinoma (LUAD), whereas these cells are undetected in normal lung and metastatic LUAD (Figure 6E)

Summary

Introduction

The prognosis for patients with small cell lung cancer (SCLC), the most aggressive lung cancer histology, remains exceptionally poor: most patients present with metastatic disease, and the recent addition of immune checkpoint blockade to firstline chemotherapy has only modestly improved median survival (Horn et al, 2018; Rudin et al, 2021). Article of four transcription factors: ASCL1, NEUROD1, POU2F3, and YAP1 (Rudin et al, 2019). This classification has led to new questions, such as whether subtypes are associated with particular disease stages, metastatic potential, or immune microenvironments, and whether there is plasticity between subtypes (Chalishazar et al, 2019; Ireland et al, 2020; Rudin et al, 2019)

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