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非肿瘤性结肠黏膜中孤立淋巴结构的免疫表型加密了转移性结直肠癌病理生物学信息。

The Immune Phenotype of Isolated Lymphoid Structures in Non-Tumorous Colon Mucosa Encrypts the Information on Pathobiology of Metastatic Colorectal Cancer.

作者信息

Mungenast Felicitas, Meshcheryakova Anastasia, Beer Andrea, Salzmann Martina, Tamandl Dietmar, Gruenberger Thomas, Pietschmann Peter, Koperek Oskar, Birner Peter, Kirsch Ilan, Robins Harlan, Mittlboeck Martina, Jaritz Markus, Bergmann Michael, Zimmermann Philip, Mechtcheriakova Diana

机构信息

Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna 1090, Austria.

Department of Pathology, Medical University of Vienna, Vienna 1090, Austria.

出版信息

Cancers (Basel). 2020 Oct 25;12(11):3117. doi: 10.3390/cancers12113117.

DOI:10.3390/cancers12113117
PMID:33113874
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7692185/
Abstract

The gut-associated lymphoid tissue represents an integral part of the immune system. Among the powerful players of the mucosa-associated lymphoid tissue are isolated lymphoid structures (ILSs), which as information centers, drive the local (and systemic) adaptive immune responses. Germinal center reactions, taking place within ILSs, involve the coordinated action of various immune cell types with a central role given to B cells. In the current study, we aimed at dissecting the impact of ILSs within non-tumorous colon tissue (NT) on the pathobiology of colorectal cancer (CRC) with metastasis in the liver (CRCLM). In particular, we focused on the immune phenotypes of ILSs and ectopic lymphoid structures (ELSs), built up at matching primary and metastatic tumor sites. We implemented an integrative analysis strategy on the basis of tissue image cytometry and clonality assessment to explore the immune phenotype of ILS/ELS at three tissue entities: NT, CRC, and CRCLM (69 specimens in total). Applying a panel of lineage markers used for immunostaining, we characterized and compared the anatomical features, the cellular composition, the activation, and proliferation status of ILSs and ELSs, and assessed the clinical relevance of staining-derived data sets. Our major discovery was that ILS characteristics at the NT site predefine the immune phenotype of ELSs at CRC and CRCLM. Thereby, B-cell-enriched (CD20) and highly proliferative (Ki67) ILSs and ELSs were found to be associated with improved clinical outcome in terms of survival and enabled patient stratification into risk groups. Moreover, the data revealed a linkage between B-cell clonality at the NT site and the metastatic characteristics of the tumor in the distant liver tissue. Consolidation of immunostaining-based findings with the results of compendium-wide transcriptomic analysis furthermore proposed CD27 as a novel marker of T follicular helper cells within lymphoid structures. Overall, the study nominates the ILS immune phenotype as a novel prognostic marker for patients with metastatic CRC.

摘要

肠道相关淋巴组织是免疫系统不可或缺的一部分。黏膜相关淋巴组织的重要组成部分是孤立淋巴结构（ILSs），它们作为信息中心，驱动局部（和全身）适应性免疫反应。发生在ILSs内的生发中心反应涉及多种免疫细胞类型的协同作用，其中B细胞起核心作用。在本研究中，我们旨在剖析非肿瘤性结肠组织（NT）中的ILSs对伴有肝转移的结直肠癌（CRCLM）病理生物学的影响。特别是，我们聚焦于在原发肿瘤和转移肿瘤匹配部位形成的ILSs和异位淋巴结构（ELSs）的免疫表型。我们基于组织图像细胞术和克隆性评估实施了综合分析策略，以探究三个组织实体（NT、CRC和CRCLM，共69个标本）中ILS/ELS的免疫表型。应用一组用于免疫染色的谱系标志物，我们对ILSs和ELSs的解剖特征、细胞组成、激活和增殖状态进行了表征和比较，并评估了染色衍生数据集的临床相关性。我们的主要发现是，NT部位的ILS特征预先确定了CRC和CRCLM中ELSs的免疫表型。因此，富含B细胞（CD20）且高度增殖（Ki67）的ILSs和ELSs在生存方面与改善的临床结局相关，并能够将患者分层为风险组。此外，数据揭示了NT部位的B细胞克隆性与远处肝组织中肿瘤转移特征之间的联系。将基于免疫染色的结果与全基因组转录组分析结果相结合，进一步提出CD27作为淋巴结构内T滤泡辅助细胞的新型标志物。总体而言，该研究将ILS免疫表型指定为转移性CRC患者的新型预后标志物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/d9d7dd118df8/cancers-12-03117-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/a84078ff03f0/cancers-12-03117-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/042f5bfb729e/cancers-12-03117-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/df06540e7337/cancers-12-03117-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/73f406c15021/cancers-12-03117-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/65d38daeffd7/cancers-12-03117-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/bf224a8190bc/cancers-12-03117-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/de49451451d5/cancers-12-03117-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/8f544834aeb5/cancers-12-03117-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/d9d7dd118df8/cancers-12-03117-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/a84078ff03f0/cancers-12-03117-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/042f5bfb729e/cancers-12-03117-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/df06540e7337/cancers-12-03117-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/73f406c15021/cancers-12-03117-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/65d38daeffd7/cancers-12-03117-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/bf224a8190bc/cancers-12-03117-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/de49451451d5/cancers-12-03117-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/8f544834aeb5/cancers-12-03117-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5f22/7692185/d9d7dd118df8/cancers-12-03117-g009.jpg

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[8]
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本文引用的文献

[1]
B cells are associated with survival and immunotherapy response in sarcoma.

Nature. 2020-1-15

[2]
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