Zhang Yueyang, Wu Deng, Zhang Zhen, Ma Jian, Jiao Shuai, Ma Xiaolong, Li Jiangtao, Meng Yongsheng, Zhao Zhixun, Chen Haipeng, Jiang Zheng, Wang Guiyu, Liu Haiyi, Xi Yanfeng, Zhou Haitao, Wang Xishan, Guan Xu
Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
College of Biomedical Information and Engineering, Hainan Medical University, Haikou, China.
Br J Cancer. 2025 Apr;132(6):513-524. doi: 10.1038/s41416-024-02921-2. Epub 2025 Jan 3.
This study aimed to investigate the prognostic impact of lymph node metastasis (LNM) on patients with colorectal cancer liver metastasis (CRLM) and elucidate the underlying immune mechanisms using multiomics profiling.
We enrolled patients with CRLM from the US Surveillance, Epidemiology, and End Results (SEER) cohort and a multicenter Chinese cohort, integrating bulk RNA sequencing, single-cell RNA sequencing and proteomics data. The cancer-specific survival (CSS) and immune profiles of the tumor-draining lymph nodes (TDLNs), primary tumors and liver metastasis were compared between patients with and without LNM. Pathological evaluations were used to assess immune cell infiltration and histological features.
The CRLM patients with LNM had significantly shorter CSS than patients without LNM in two large cohorts. Our results showed that nonmetastatic TDLNs exhibited a greater abundance of immune cells, including CD4+ T cells, CD8+ T cells, and CD19+ B cells, whereas metastatic TDLNs were enriched with fibroblasts, endothelial cells, and macrophages. Immunohistochemical analysis confirmed elevated levels of CD3+ T cells, CD8+ T cells, and CD19+ B cells in nonmetastatic TDLNs. The presence of nonmetastatic TDLNs was associated with enhanced antitumor immune responses in primary tumors, characterized by a higher Klintrup-Makinen (KM) grade and the presence of tertiary lymphoid structures. Furthermore, liver metastasis in patients with nonmetastatic TDLNs were predominantly of the desmoplastic growth pattern (dHGP), while those with metastatic TDLNs were predominantly of the replacement growth pattern (rHGP).
This research highlights the adverse prognostic impact of LNM on patients with CRLM and reveals potential related mechanisms through multiomics analysis. Our research paves the way for further refinement of the AJCC TNM staging system for CRLM in clinical practice.
本研究旨在探讨淋巴结转移（LNM）对结直肠癌肝转移（CRLM）患者预后的影响，并通过多组学分析阐明潜在的免疫机制。
我们纳入了来自美国监测、流行病学和最终结果（SEER）队列以及一个中国多中心队列的CRLM患者，整合了批量RNA测序、单细胞RNA测序和蛋白质组学数据。比较了有和没有LNM的患者之间肿瘤引流淋巴结（TDLN）、原发性肿瘤和肝转移的癌症特异性生存率（CSS）和免疫谱。采用病理评估来评估免疫细胞浸润和组织学特征。
在两个大型队列中，有LNM的CRLM患者的CSS明显短于没有LNM的患者。我们的结果表明，非转移性TDLN表现出更丰富的免疫细胞，包括CD4 + T细胞、CD8 + T细胞和CD19 + B细胞，而转移性TDLN富含成纤维细胞、内皮细胞和巨噬细胞。免疫组织化学分析证实非转移性TDLN中CD3 + T细胞、CD8 + T细胞和CD19 + B细胞水平升高。非转移性TDLN的存在与原发性肿瘤中抗肿瘤免疫反应增强相关，其特征是较高的克林特鲁普 - 马基宁（KM）分级和三级淋巴结构的存在。此外，有非转移性TDLN的患者的肝转移主要为促结缔组织增生性生长模式（dHGP），而有转移性TDLN的患者的肝转移主要为替代生长模式（rHGP）。
本研究强调了LNM对CRLM患者的不良预后影响，并通过多组学分析揭示了潜在的相关机制。我们的研究为临床实践中进一步完善CRLM的美国癌症联合委员会（AJCC）TNM分期系统铺平了道路。
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