Deng Chaoqiang, Wang Yue, Fu Fangqiu, Li Di, Zheng Qiang, Jin Yan, Li Yuan, Chen Haiquan, Zhang Yang
Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering Fudan University Shanghai Cancer Center Shanghai China.
Institute of Thoracic Oncology Fudan University Shanghai China.
MedComm (2020). 2023 Oct 1;4(5):e370. doi: 10.1002/mco2.370. eCollection 2023 Oct.
Despite recent progress in subtype classification for small cell lung carcinoma (SCLC), little is known about the biomarker for triple-negative (ASCL1, NEUROD1, and POU2F3 negative) tumors. The long-term survival, adjuvant chemotherapy (ACT) response, and immune milieu in different SCLC subtypes have also not been well established. Here, we retrospectively collected a large cohort of 192 primary SCLC tumors and reported that ASCL1-, NEUROD1- and POU2F3-dominant subtypes counted for 61.38%, 19.31%, and 6.21%, respectively. Subtype intra-tumoral heterogeneity and co-expression at the single-cell level existed substantially. The expression of tumor-derived Vimentin (VIM) was nearly restricted to triple-negative SCLC tumors (15/19, 78.9%) while YAP1 expression was distributed widely in other subtypes. The SCLC subtyping model was independently prognostic of OS and RFS ( < 0.001 and = 0.043). In particular, patients with ASCL1-positive SCLC tumors can benefit more from ACT, and VIM-positive tumors did the opposite. Compared with other subtypes, the VIM-dominant SCLC subtype was associated with abundant but functionally impaired CD4 and CD8 T-cells, which highly expressed inhibitory checkpoints and potentially benefit from PD-L1 blockade therapy. Our study showed that tumor-derived SCLC-V subtype could independently predict ACT response. The distinct immune landscape between subtypes may help inform personalized immune therapeutic approaches.
尽管小细胞肺癌(SCLC)的亚型分类最近取得了进展,但对于三阴性(ASCL1、NEUROD1和POU2F3阴性)肿瘤的生物标志物仍知之甚少。不同SCLC亚型的长期生存、辅助化疗(ACT)反应和免疫环境也尚未明确。在此,我们回顾性收集了192例原发性SCLC肿瘤的大型队列,并报告ASCL1主导型、NEUROD1主导型和POU2F3主导型亚型分别占61.38%、19.31%和6.21%。亚型内肿瘤异质性和单细胞水平的共表达大量存在。肿瘤源性波形蛋白(VIM)的表达几乎仅限于三阴性SCLC肿瘤(15/19,78.9%),而YAP1表达在其他亚型中广泛分布。SCLC亚型分类模型对总生存期(OS)和无复发生存期(RFS)具有独立的预后价值(<0.001和=0.043)。特别是,ASCL1阳性SCLC肿瘤患者可从ACT中获益更多,而VIM阳性肿瘤患者则相反。与其他亚型相比,VIM主导型SCLC亚型与丰富但功能受损的CD4和CD8 T细胞相关,这些细胞高表达抑制性检查点,可能从PD-L1阻断治疗中获益。我们的研究表明,肿瘤源性SCLC-V亚型可独立预测ACT反应。亚型之间独特的免疫格局可能有助于指导个性化免疫治疗方法。