Integrated spatial transcriptomic profiling to dissect the cellular characteristics of tumor-associated tertiary lymphoid structures

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.

Keywords: CCL19+ perivascular cell; CP: Cancer; CP: Immunology; IgG+ plasma cells; high endothelial venule; lymphoid tissue organizer; spatial transcriptomics; tumor-associated tertiary lymphoid structures.