Lymph nodes molecular subtypes unravel lymph nodes heterogeneity and clinical implications in colorectal cancer
Xu Guan, Yueyang Zhang, Ruifang Sun, Guiyu Wang, Xiaoman Bi, Zhen Zhang, L K Zan, Yongsheng Meng, Yunxiao Liu, Jinyuan Guo, Jianhua Ma, Jinchen Li, Hanqing Hu, Yixun Zhang, Xin Zhang, Maoxi Liu, Bo Jiang, Haiyi Liu, Shuangmei Zou, Yanfeng Xi, Haitao Zhou, Wenqi Bai, Deng Wu, Xishan Wang
Abstract
Lymph nodes (LNs) play a pivotal role in colorectal cancer (CRC) progression and immunity, yet their molecular and functional diversity remains poorly understood. By analyzing 630 LNs and 88 primary tumors from 200 CRC patients across four independent cohorts using bulk and single-cell RNA sequencing, we identify four non-metastatic negative LNs (NLN) subtypes (NLN_C1-C4) exhibiting obviously different immune function and stromal expansion. NLN_C3/C4 are characterized by diminished T and B cell activity and fibroblast-driven fibrosis, with follicular dendritic cell loss contributing to B cell dysfunction. Immune checkpoint inhibitors partially reverse these effects, restoring FDC and B cell activity. LNs subtypes demonstrate heterogeneity across patients and within individuals, with higher NLN_C3/C4 proportions associated with advanced tumor stages, poorer survival, and recurrence. Here, we report LNs subtypes as critical manifestations of LN heterogeneity in CRC, providing a basis for improved clinical stratification and LN-targeted therapeutic strategies. Lymph nodes are primarily categorised into metastatic and non-metastatic. Here, the authors perform integrated bulk and single-cell RNA sequencing on lymph nodes from 200 patients with colorectal cancer and identify 4 non-metastatic lymph node subtypes.