PO.TB10.02 · 肿瘤生物学
肿瘤引流淋巴结的单细胞与空间整合图谱揭示转移相关的基质与免疫重塑
Integrated single-cell and spatial atlas of tumor-draining lymph nodes reveals metastasis-associated stromal and immune remodeling
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摘要 Abstract
中文摘要
引言：肿瘤引流淋巴结（TDLNs）是抗肿瘤免疫的关键部位，也是免疫治疗的重要靶点。然而，它们也是肿瘤播散的早期部位，且淋巴结定植的转移性肿瘤与其原发对应病灶相比，对免疫治疗的反应性降低。转移如何重塑TDLN的基质-免疫生态系统仍未得到充分研究。
方法：我们利用单细胞RNA测序（scRNA-seq）和空间转录组学（ST），构建了一个泛癌种TDLN图谱，涵盖来自15种癌症、70名供者的健康淋巴结（hLN）、非转移性TDLN（nLN）和转移性TDLN（mLN）的超过100万个细胞。关键发现在独立患者标本和小鼠模型中得到验证。
结果：我们的整合分析构建了一个名为PanTDLN的公共资源，其鉴定出髓系细胞、基质细胞和T细胞是转移后改变最显著的细胞群，具有缺氧、激活和耗竭等特征。在空间上，鉴定出转移后形成的四种跨癌种生态位：初始细胞富集区、肿瘤反应区、瘤周区和转移肿瘤区，各具不同的细胞组成和配体-受体网络。初始细胞富集区充满初始T/B细胞以及PD-1+ CXCL13+辅助性T细胞，并富集免疫招募和激活性趋化因子轴。瘤周生态位由一种独特的屏障形成型成纤维网状细胞（FRC）构建，其具有最强的细胞外基质重塑程序，将富含抗原提呈细胞和细胞毒性淋巴细胞的肿瘤反应生态位与肿瘤块在空间上隔离开来。在肿瘤生态位内，缺氧相关巨噬细胞和单核细胞（HAMs）被特异性富集，导致瘤内免疫荒漠。同时，这些HAMs通过TNF-TNFR轴促使肿瘤反应生态位内的调节性T细胞（Tregs）向终末分化表型转变，从而导致肿瘤反应生态位中激活的细胞毒性T/NK细胞功能障碍。动物模型证明，靶向屏障形成型FRCs以及HAMs与Tregs之间的通讯，可破坏基质-免疫重塑并增强mLN中的免疫治疗反应。
结论：PanTDLN解码了TDLN转移过程中的时空基质-免疫重塑，并提供了潜在的跨癌种治疗靶点，有助于淋巴结阳性癌症患者的治疗。
查看英文原文 English abstract
Introduction: Tumor-draining lymph nodes (TDLNs) are critical sites for anti-tumor immunity and important targets of immunotherapy. However, they are also early sites of tumor dissemination, and lymph node-resident metastatic tumors exhibit reduced responsiveness to immunotherapy compared with their primary counterparts. How metastasis reshapes TDLN stromal-immune ecosystems remains underexplored.
Methods: We built a pan-cancer TDLN atlas, which consists of >1 million cells from healthy lymph nodes (hLN), non-metastatic TDLNs (nLN), and metastatic TDLNs (mLN) across 15 cancers and 70 donors using single-cell RNA sequence (scRNA-seq) and spatial transcriptomics (ST). Key findings were validated in independent patient specimens and mouse models.
Result: Our integrated analysis constructed a public resource named PanTDLN, which identifies myeloid cells, stromal cells, and T cells as the most altered populations after metastasis, with characteristics including hypoxia, activation, and exhaustion. Spatially, four cross-cancer niches that form after metastasis are identified: naïve-enriched, tumor-reactive, peritumoral, and metastatic tumor, each with distinct cellular compositions and ligand-receptor networks. Naïve-enriched zones are filled with naïve T/B cells and PD-1+ CXCL13+ T helper cells with enrichment of immune-recruiting and activating chemokine axes. Peritumoral niches are built by a unique barrier-forming fibroblastic reticular cell (FRC) with the strongest extracellular matrix remodeling program, which spatially segregates the tumor-reactive niche, rich in antigen-presenting cells and cytotoxic lymphocytes, from the tumor mass. Within the tumor niches, hypoxia-associated macrophages and monocytes (HAMs) are specifically enriched, leading to an intratumoral immune desert. Meanwhile, these HAMs promote regulatory T cells (Tregs) within tumor-reactive niches toward terminally differentiated phenotypes via the TNF-TNFR axis, resulting in dysfunction of activated cytotoxic T/NK cells in the tumor-reactive niche. Animal models prove that targeting barrier-forming FRCs and the communication between HAMs and Tregs can disrupt the stromal-immune remodeling and enhance immunotherapy response in mLNs.
Conclusion: PanTDLN decodes the spatiotemporal stromal-immune remodeling during TDLN metastasis and provides potential cross-cancer therapeutic targets, facilitating the treatment of lymph node-positive cancer patients.
利益披露 Disclosure
E. Zhang, None..
L. Zhang, None..
H. Yang, None..
F. Yao, None.