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

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 TLSs and SLOs. In RNA expression analyses of laser-microdissected TLSs 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 TLSs 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 TLSs and SLOs, 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.