Atezolizumab (anti-PD-L1), combined with carboplatin and etoposide (CE), is now a standard of care for extensive-stage small-cell lung cancer (ES-SCLC). A clearer understanding of therapeutically relevant SCLC subsets could identify rational combination strategies and improve outcomes. We conduct transcriptomic analyses and non-negative matrix factorization on 271 pre-treatment patient tumor samples from IMpower133 and identify four subsets with general concordance to previously reported SCLC subtypes (SCLC-A, -N, -P, and -I). Deeper investigation into the immune heterogeneity uncovers two subsets with differing neuroendocrine (NE) versus non-neuroendocrine (non-NE) phenotypes, demonstrating immune cell infiltration hallmarks. The NE tumors with low tumor-associated macrophage (TAM) but high T-effector signals demonstrate longer overall survival with PD-L1 blockade and CE versus CE alone than non-NE tumors with high TAM and high T-effector signal. Our study offers a clinically relevant approach to discriminate SCLC patients likely benefitting most from immunotherapies and highlights the complex mechanisms underlying immunotherapy responses.

中文翻译：

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小细胞肺癌的免疫异质性和免疫检查点封锁的脆弱性

Atezolizumab（抗 PD-L1）与卡铂和依托泊苷 (CE) 联合使用现已成为广泛期小细胞肺癌 (ES-SCLC) 的标准治疗方法。更清楚地了解治疗相关的 SCLC 子集可以确定合理的联合策略并改善结果。我们对来自 IMpower133 的 271 例治疗前患者肿瘤样本进行转录组分析和非负矩阵分解，并确定了与之前报告的 SCLC 亚型（SCLC-A、-N、-P 和 -I）总体一致的四个子集。对免疫异质性的深入研究发现了两个具有不同神经内分泌（NE）与非神经内分泌（non-NE）表型的子集，证明了免疫细胞浸润特征。与具有高 TAM 和高 T 效应器信号的非 NE 肿瘤相比，具有低肿瘤相关巨噬细胞 (TAM) 但高 T 效应器信号的 NE 肿瘤在 PD-L1 阻断和 CE 的情况下表现出更长的总生存期。我们的研究提供了一种临床相关的方法来区分可能从免疫治疗中获益最多的 SCLC 患者，并强调了免疫治疗反应背后的复杂机制。