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.
摘要：
三级淋巴结构（TLSs）与肿瘤中增强的免疫力有关。然而,它们在结直肠癌肝转移（CRLM）中的形成和功能尚不清楚。这里,我们发现,与TLS-肿瘤相比,肿瘤内和肿瘤周围成熟的TLS(TLS+)与改善的临床结局相关.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-肿瘤的特征在于IgA+PC。通过体外生成TLS相关PC衍生的单克隆抗体，我们显示TLS-PC分泌肿瘤靶向抗体。作为概念证明，我们证明了TLS-PC-mAb6抗体在人源化结直肠癌小鼠模型中的抗肿瘤活性。我们确定了分泌CCL19的成纤维细胞谱系，可促进淋巴细胞向TLS的运输。CCL19治疗促进TLS新生并防止小鼠肿瘤生长。我们的数据揭示了CCL19+成纤维细胞在TLS形成中的核心作用，进而产生治疗性抗体以限制CRLM。
