Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer.

IF 13 1区 生物学 Q1 CELL BIOLOGY
Ying Jin, Yuefeng Wu, Alexandre Reuben, Liang Zhu, Carl M Gay, Qingzhe Wu, Xintong Zhou, Haomin Mo, Qi Zheng, Junyu Ren, Zhaoyuan Fang, Teng Peng, Nan Wang, Liang Ma, Yun Fan, Hai Song, Jianjun Zhang, Ming Chen
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Abstract

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.

Abstract Image

单细胞和空间蛋白质转录组特征分析揭示了与小细胞肺癌神经内分泌特征相关的免疫浸润异质性。
小细胞肺癌(SCLC)是一种侵袭性肺神经内分泌恶性肿瘤,其特点是肿瘤免疫微环境(TIME)寒冷、免疫疗法获益有限且生存率低。目前尚未对 SCLC 中与抗肿瘤免疫显著相关的 TIME 空间异质性进行系统研究。我们对来自 44 例未接受治疗的局限期 SCLC 肿瘤的 132 个组织芯片核进行了超高倍数字空间谱分析。结合来自本地队列的单细胞 RNA 序列数据和已发表的 SCLC 数据,我们建立了一个空间蛋白质转录组图谱,涵盖了 18,000 多个基因和 60 个关键免疫肿瘤学蛋白,这些蛋白参与了影响肿瘤发生、免疫调节和癌症代谢的信号通路,横跨 3 个病理学定义的空间分区(pan-CK 阳性瘤巢;CD45/CD3 阳性肿瘤基质;瘤旁)。我们的研究描绘了SCLC的空间转录组和蛋白质组TIME结构,表明通过典型神经内分泌亚型标志物决定的肿瘤内异质性;揭示了先天性免疫细胞和功能受损的B细胞在肿瘤巢中的富集,并提出了单核细胞/巨噬细胞潜在的重要免疫调节作用。我们发现RE1沉默因子(REST)是SCLC的潜在生物标志物,它与低神经内分泌特征、更活跃的抗肿瘤免疫和生存期延长有关。
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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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