Jin Ying, Wu Yuefeng, Reuben Alexandre, Zhu Liang, Gay Carl M, Wu Qingzhe, Zhou Xintong, Mo Haomin, Zheng Qi, Ren Junyu, Fang Zhaoyuan, Peng Teng, Wang Nan, Ma Liang, Fan Yun, Song Hai, Zhang Jianjun, Chen Ming
Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang, China.
Cell Discov. 2024 Sep 4;10(1):93. doi: 10.1038/s41421-024-00703-x.
Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.
小细胞肺癌（SCLC）是一种侵袭性肺神经内分泌恶性肿瘤，其特征为冷肿瘤免疫微环境（TIME）、免疫治疗获益有限且生存率低。TIME与抗肿瘤免疫显著相关的空间异质性在SCLC中尚未得到系统研究。我们对来自44例未经治疗的局限期SCLC肿瘤的132个组织微阵列芯进行了超高通量数字空间分析。结合来自本地队列的单细胞RNA测序数据和已发表的SCLC数据，我们建立了一个空间蛋白质组-转录组图谱，涵盖超过18,000个基因和60种关键免疫肿瘤学蛋白质，这些蛋白质参与影响肿瘤发生、免疫调节和癌症代谢的信号通路，跨越3个病理定义的空间区室（泛细胞角蛋白阳性肿瘤巢；CD45/CD3阳性肿瘤基质；肿瘤旁组织）。我们的研究描绘了SCLC的空间转录组和蛋白质组TIME结构，表明通过经典神经内分泌亚型标志物决定了明显的肿瘤内异质性；揭示了肿瘤巢中固有免疫细胞和功能受损B细胞的富集，并提示单核细胞/巨噬细胞可能具有重要的免疫调节作用。我们确定RE1沉默因子（REST）作为SCLC的潜在生物标志物，其与低神经内分泌特征、更活跃的抗肿瘤免疫和延长生存期相关。
