单细胞整合与多模态分析揭示结直肠癌中中性粒细胞的表型和空间组织

Single-cell integration and multi-modal profiling reveals phenotypes and spatial organization of neutrophils in colorectal cancer.

作者信息

Marteau Valentin, Nemati Niloofar, Handler Kristina, Raju Deeksha, Kirchmair Alexander, Rieder Dietmar, Kvalem Soto Erika, Fotakis Georgios, De Lange Glenn, Carollo Sandro, Boeck Nina, Rossi Alessia, Daum Sophia, Scheiber Alexandra, Amann Arno, Seeber Andreas, Gasser Elisabeth, Ormanns Steffen, Günther Michael, Martowicz Agnieszka, Loncova Zuzana, Lamberti Giorgia, Krogsdam Anne, Carlet Michela, Horvath Lena, Eling Marie Theres, Fazilaty Hassan, Valenta Tomas, Sturm Gregor, Sopper Sieghart, Pircher Andreas, Stoitzner Patrizia, Wild Peter J, Welker Patrick, May Pascal J, Ziegler Paul, Tschurtschenthaler Markus, Neureiter Daniel, Huemer Florian, Greil Richard, Weiss Lukas, Ijsselsteijn Marieke, de Miranda Noel F C C, Wolf Dominik, Arnold Isabelle C, Salcher Stefan, Trajanoski Zlatko

机构信息

Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

出版信息

Cancer Cell. 2026 Jan 12;44(1):146-165.e14. doi: 10.1016/j.ccell.2025.12.003.

DOI:10.1016/j.ccell.2025.12.003

PMID:41529665

Abstract

The immune composition of the tumor microenvironment has a major impact on the therapy response in patients with colorectal cancer. Here, we built an atlas with 4.27 million single cells from 1,670 patient samples and complemented it with single-cell profiles from 266 patients, including cells with low mRNA content, spatial transcriptomics from 3.7 million cells, and protein profiles from 0.7 million cells. The analysis of the atlas allows tumor classification into immune desert, B cell enriched, T cell enriched, and myeloid cell enriched immune phenotypes. Within the myeloid compartment, we identify consensus myeloid gene expression programs with four immunomodulatory programs, and uncover a subpopulation of neutrophils with antigen-presenting properties. Moreover, functional experiments using patient-derived organoids show KRAS-dependent pro-tumorigenic polarization of neutrophils. Further, spatial multimodal single-cell profiling reveals niches with IL-1 signaling-based neutrophil-fibroblast interaction. Finally, using an orthotopic mouse model, we show that cancer-derived signals modify neutrophil production in the bone marrow.

摘要

肿瘤微环境的免疫组成对结直肠癌患者的治疗反应有重大影响。在此，我们构建了一个包含来自1670例患者样本的427万个单细胞的图谱，并补充了来自266例患者的单细胞图谱，包括低mRNA含量的细胞、来自370万个细胞的空间转录组学数据以及来自70万个细胞的蛋白质图谱。对该图谱的分析可将肿瘤分为免疫荒漠型、B细胞富集型、T细胞富集型和髓系细胞富集型免疫表型。在髓系细胞区室中，我们鉴定出具有四种免疫调节程序的一致性髓系基因表达程序，并发现了具有抗原呈递特性的中性粒细胞亚群。此外，使用患者来源类器官的功能实验表明，中性粒细胞的促肿瘤极化依赖于KRAS。进一步地，空间多模态单细胞分析揭示了基于IL-1信号的中性粒细胞与成纤维细胞相互作用的微环境。最后，使用原位小鼠模型，我们表明癌症衍生信号会改变骨髓中中性粒细胞的生成。