少数广泛期小细胞肺癌 (ES-SCLC) 患者在一线化学免疫治疗后表现出延长的生存期，这需要使用可靠的生物标志物。在这里，我们调查了 ES-SCLC 患者长期和短期生存之间基因组学和免疫细胞空间分布的差异。我们回顾性招募了 11 名长期（> 2 年）和 13 名短期（< 9 个月）患者接受一线化学免疫治疗的 ES-SCLC 幸存者。使用靶向下一代测序 (tNGS)、程序性死亡配体-1 染色、免疫细胞多重免疫组织化学染色 (mIHC)、肿瘤突变负荷 (TMB) 和染色体不稳定评分测量来处理样本。分析了 SCLC 中推定基因在整体和单细胞 RNA 测序水平上的表达，以及推定基因在泛癌免疫治疗队列中的作用。在基因组水平上，吸烟特征和吸烟特征的比例更大。较高的 TMB (>3.1) 与良好的生存相关。在单基因和通路水平上，tNGS 显示 MCL1 和 STMN1 扩增以及细胞凋亡通路的改变在短期幸存者中更为常见，而 DLL3、KMT2B、HGF、EPHA3、ADGRB3、赖氨酸剥夺和 HGF 的改变-cMET 途径在长期幸存者中更常见。对不同空间分布的免疫细胞的 mIHC 分析显示，长期存活者在所有位置呈现 M1 样巨噬细胞数量增加，而肿瘤基质中 CD8 T 细胞数量减少。大量转录组分析表明，高水平的 STMN1 和 DLL3 代表免疫抑制性肿瘤免疫微环境 (TIME)，而 HGF 则表明免疫反应性 TIME。我们假定的基因的表达水平在 TP53/RB1 突变型和 TP53/RB1 野生型中是可比较的。在单细胞水平上，STMN1、MCL1和DLL3在所有分子亚型（SCLC-A、SCLC-N和SCLC-P）中高表达，其中STMN1在细胞分裂和G2M检查点通路中富集。对于ES-接受一线化学免疫治疗的 SCLC 患者，DLL3、KMT2B、HGF、EPHA3 和 ADGRB3 的改变以及所有位置 M1 样巨噬细胞浸润比例较高是有利生存的预测因素，而 MCL1 和 STMN1 扩增以及更大比例的 M1 样巨噬细胞浸润是有利生存的预测因素。 CD8 T 细胞浸润肿瘤基质的比例，预测生存率较差。版权所有 © 2024 Elsevier B.V. 保留所有权利。

A minority of patients with extensive-stage small cell lung cancer (ES-SCLC) exhibit prolonged survival following first-line chemoimmunotherapy, which warrants the use of reliable biomarkers. Here, we investigated the disparities in genomics and immune cell spatial distribution between long- and short-term survival of patients with ES-SCLC.We retrospectively recruited 11 long-term (>2 years) and 13 short-term (<9 months) ES-SCLC survivors receiving first-line chemoimmunotherapy. The samples were processed using targeted next-generation sequencing (tNGS), programmed death ligand-1 staining, multiplex immunohistochemical staining for immune cells (mIHC), tumor mutation burden (TMB), and chromosomal instability score measurements. The expression of putative genes in SCLC at the bulk and single-cell RNA-sequencing levels, as well as the role of putative genes in pan-cancer immunotherapy cohorts, were analyzed.At the genomic level, a greater proportion of the smoking signature and higher TMB (>3.1) were associated with favorable survival. At the single-gene and pathway levels, tNGS revealed that MCL1 and STMN1 amplification and alterations in the apoptosis pathway were more common in short-term survivors, whereas alterations in the DLL3, KMT2B, HGF, EPHA3, ADGRB3, lysine deprivation, and HGF-cMET pathways were observed more frequently in long-term survivors. mIHC analysis of immune cells with different spatial distributions revealed that long-term survivors presented increased numbers of M1-like macrophages in all locations and decreased numbers of CD8+ T cells in the tumor stroma. Bulk transcriptomic analysis demonstrated that high levels of STMN1 and DLL3 represented an immune-suppressive tumor immune microenvironment (TIME), whereas HGF indicated an immune-responsive TIME. The expression levels of our putative genes were comparative in both TP53/RB1 mutant-type and TP53/RB1 wild-type. At the single-cell level, STMN1, MCL1, and DLL3 were highly expressed among all molecular subtypes (SCLC-A, SCLC-N, and SCLC-P), with STMN1 being enriched in cell division and G2M checkpoint pathways.For ES-SCLC patients receiving first-line chemoimmunotherapy, alterations in DLL3, KMT2B, HGF, EPHA3, and ADGRB3 and a greater proportion of M1-like macrophages infiltration in all locations were predictors of favorable survival, while MCL1 and STMN1 amplification, as well as a greater proportion of CD8+ T cells infiltrating the tumor stroma, predicted worse survival.Copyright © 2024 Elsevier B.V. All rights reserved.