Integrated spatial transcriptomic profiling to dissect the cellular characteristics of tumor-associated tertiary lymphoid structures
Xiangjie Li, Xiaojing Chu, Wenbin Xu, Yi Yang, Ting Wei, Yufei Bo, Yuhui Miao, Yu Zhang, Jinyu Wang, Teng Wang, Guohui Dang, Qi Lu, Dan Cacsire Castillo‐Tong, Linnan Zhu, Hong Zhao, Zemin Zhang, Sijin Cheng
Abstract
The presence and maturation of tumor-associated tertiary lymphoid structures (TA-TLSs) significantly influence immune activation and clinical outcome. We integrated spatial transcriptomics data across 23 cancers to construct a pan-cancer TA-TLS atlas, revealing cellular dynamics and spatial organization under different maturation states. We revealed a preferential enrichment of IgG+ plasma cells in mature TLSs, and both in silico and in vitro analyses consistently revealed that the identified CCL19+ perivascular cells may act as lymphoid tissue organizer cells associated with TA-TLS formation. Additionally, we observed the presence of arterial endothelial cells within TA-TLSs, which could acquire high endothelial venule-like phenotypes in response to Notch signaling inhibition, with enhanced immune recruiting capacity. Our results provide a comprehensive cellular dissection of TA-TLSs and shed light on the mechanisms of TA-TLS formation and maturation, which hold promise in prioritizing therapeutic strategies targeting TLS, with the potential to transform poor prognostic tumors into immunogenic tumors.