Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10016, USA.
Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cancer Cell. 2021 Nov 8;39(11):1479-1496.e18. doi: 10.1016/j.ccell.2021.09.008. Epub 2021 Oct 14.
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 T cell 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.
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，包括 ASCL1、NEUROD1 和 POU2F3 表达差异定义的亚型（分别为 SCLC-A、-N 和 -P）。为了定义不同亚型肿瘤及其相关微环境的异质性，我们对 21 个人类生物样本中的 155,098 个转录组进行了测序，其中包括 54,523 个 SCLC 转录组。我们观察到 SCLC 中的肿瘤多样性比肺腺癌更大，这是由典型、中间和混合亚型驱动的。我们发现一种 PLCG2 高表达的 SCLC 表型，具有干细胞样、促转移的特征，在不同亚型中反复出现，并预测总体生存率更差。与肺腺癌相比，SCLC 表现出更大的免疫隔离和更少的免疫浸润，而 SCLC-N 比 SCLC-A 表现出更少的免疫浸润和更大的 T 细胞功能障碍。我们在 SCLC 肿瘤中发现了一种促纤维化、免疫抑制的单核细胞/巨噬细胞群体，该群体与复发性、PLC2 高表达亚群特别相关。
