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.
Cancer Cell. 2024 Aug 12;42(8):1370-1385.e9. doi: 10.1016/j.ccell.2024.07.006.
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.
三级淋巴结构 (TLSs) 与肿瘤中的增强免疫有关。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 TLSs（TLS+）与改善的临床结果相关，而 TLS-肿瘤则不然。通过单细胞 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 (PCs)，而 TLS-肿瘤的特征是 IgA PCs。通过在体外生成与 TLS 相关的 PC 衍生的单克隆抗体，我们表明 TLS-PC 分泌靶向肿瘤的抗体。作为概念验证，我们在结直肠癌的人源化小鼠模型中证明了 TLS-PC-mAb6 抗体的抗肿瘤活性。我们确定了一种分泌 CCL19 的成纤维细胞谱系，它有助于淋巴细胞向 TLS 的迁移。CCL19 治疗促进了 TLS 的新生，并防止了小鼠的肿瘤生长。我们的数据揭示了 CCL19 成纤维细胞在 TLS 形成中的核心作用，而 TLS 反过来又产生治疗性抗体来限制 CRLM。
