Tertiary lymphoid structures in pancreatic cancer are structurally homologous, share gene expression patterns and B-cell clones with secondary lymphoid organs but show increased T-cell activation.

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Tertiary lymphoid structures (TLS) in cancer are considered ectopic hotspots for immune activation that are similar to lymphoid follicles in secondary lymphoid organs (SLO). This study elucidates shared and TLS/SLO-specific features in pancreatic ductal adenocarcinoma (PDAC). TLS abundance was related to superior survival and T-cell abundance in 110 treatment-naïve PDAC samples, underlining their clinical relevance. Immunofluorescence microscopy identified structural homologies between TLS and SLO. In RNA-expression analyses of laser-microdissected TLS and paired SLOs, we observed largely overlapping expression patterns of immune-related gene clusters, but distinct expression patterns of T-cell and complement-associated genes. Immune cells in TLS expressed essential markers of germinal center formation. Increased activation of tumor-draining lymph nodes in patients with high numbers of TLS highlights the relevance of these tumor-related structures to systemic immune response. In line with this, we identified an overlap of expanded B-cell receptor clonotypes in TLS and SLO, which suggests a vivid cross-talk between the two compartments. . We conclude that combined therapeutic approaches exploiting TLS-mediated antitumor immune responses may improve susceptibility of PDAC to immunotherapy.