CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis

IF 48.8 1区 医学 Q1 CELL BIOLOGY Cancer Cell Pub Date : 2024-08-12 DOI:10.1016/j.ccell.2024.07.006
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Abstract

Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS− tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS− tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.

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产生 CCL19 的成纤维细胞可促进三级淋巴结构的形成,增强结直肠癌肝转移中的抗肿瘤 IgG 反应
三级淋巴结构(TLS)与肿瘤免疫力增强有关。然而,它们在结直肠癌肝转移(CRLM)中的形成和功能仍不清楚。在这里,我们揭示了肿瘤内和肿瘤周围成熟的 TLS(TLS+)比 TLS- 肿瘤更能改善临床预后。利用单细胞-RNA 测序和空间增强分辨组学测序(Stereo-seq),我们发现TLS+肿瘤富含IgG+浆细胞(PCs),而TLS-肿瘤则以IgA+ PCs为特征。通过在体外生成 TLS 相关 PC 衍生的单克隆抗体,我们发现 TLS-PCs 会分泌肿瘤靶向抗体。作为概念验证,我们在人源化小鼠结直肠癌模型中证明了 TLS-PC-mAb6 抗体的抗肿瘤活性。我们发现成纤维细胞系分泌的 CCL19 可促进淋巴细胞向 TLS 转移。CCL19 治疗可促进小鼠 TLS 的新生并阻止肿瘤生长。我们的数据揭示了CCL19+成纤维细胞在TLS形成中的核心作用,这反过来又产生了限制CRLM的治疗性抗体。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
期刊介绍: Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.
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