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

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CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis
Cancer Cell ( IF 48.8 ) Pub Date : 2024-08-12 , DOI: 10.1016/j.ccell.2024.07.006
Yifan Zhang ₁ , Guangjian Liu ₂ , Qianwen Zeng ₁ , Wenrui Wu ₃ , Kai Lei ₄ , Chuankai Zhang ₅ , Miaoling Tang ₆ , Yuting Zhang ₇ , Xiao Xiang ₁ , Li Tan ₁ , Rui Cui ₂ , Si Qin ₂ , Xinming Song ₄ , Changjun Yin ₈ , Zhihang Chen ₁ , Ming Kuang ₉

Affiliation

Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Department of Medical Ultrasonics, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, 80336 Munich, Germany.
Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China; Sun Yat-sen University Zhongshan School of Medicine, Guangzhou 510080, China.

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 , 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.

中文翻译：

产生CCL19的成纤维细胞促进三级淋巴结构形成，增强结直肠癌肝转移中的抗肿瘤IgG反应

三级淋巴结构（TLS）与肿瘤免疫力的增强有关。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，我们发现肿瘤内和肿瘤周围的成熟 TLS (TLS+) 与 TLS- 肿瘤相比改善的临床结果相关。使用单细胞 RNA 测序和空间增强分辨率组学测序 (Stereo-seq)，我们发现 TLS+ 肿瘤富含 IgG 浆细胞 (PC)，而 TLS− 肿瘤则富含 IgA PC。通过生成 TLS 相关的 PC 衍生的单克隆抗体，我们表明 TLS-PC 可以分泌肿瘤靶向抗体。作为概念验证，我们在结直肠癌人源化小鼠模型中证明了 TLS-PC-mAb6 抗体的抗肿瘤活性。我们鉴定出分泌 CCL19 的成纤维细胞谱系，可促进淋巴细胞转运至 TLS。 CCL19 治疗可促进小鼠 TLS 新生并防止肿瘤生长。我们的数据揭示了 CCL19 成纤维细胞在 TLS 形成中的核心作用，TLS 形成反过来又产生治疗性抗体来限制 CRLM。

更新日期：2024-08-12

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