Lehmann Jonas, Thelen Martin, Kreer Christoph, Schran Simon, Garcia-Marquez Maria A, Cisic Igor, Siepmann Klara, Hagen Elena M, Eckel Hans Nikolaus Caspar, Lohneis Philipp, Kruger Stephan, Boeck Stefan, Ormanns Steffen, Rudelius Martina, Werner Jens, Popp Felix, Klein Florian, von Bergwelt-Baildon Michael S, Bruns Christiane J, Quaas Alexander, Wennhold Kerstin, Schlößer Hans A
Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Laboratory of Experimental Immunology, Faculty of Medicine and University Hospital Cologne, Institute of Virology, University of Cologne Cologne, Germany.
Cancer Immunol Res. 2025 Mar 4;13(3):323-336. doi: 10.1158/2326-6066.CIR-24-0299.
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.
癌症中的三级淋巴结构（TLS）被认为是免疫激活的异位热点，类似于二级淋巴器官（SLO）中的淋巴滤泡。本研究阐明了胰腺导管腺癌（PDAC）中TLS和SLO共有的以及TLS/SLO特有的特征。在110例未经治疗的PDAC样本中，TLS丰度与较好的生存率和T细胞丰度相关，突显了它们的临床相关性。免疫荧光显微镜检查确定了TLS和SLO之间的结构同源性。在对激光显微切割的TLS和配对的SLO进行RNA表达分析时，我们观察到免疫相关基因簇的表达模式基本重叠，但T细胞和补体相关基因的表达模式不同。TLS中的免疫细胞表达生发中心形成的关键标志物。TLS数量较多的患者肿瘤引流淋巴结的激活增加，突显了这些肿瘤相关结构与全身免疫反应的相关性。与此一致的是，我们在TLS和SLO中发现了扩增的B细胞受体克隆型的重叠，这表明两个区室之间存在活跃的相互作用。我们得出结论，利用TLS介导的抗肿瘤免疫反应的联合治疗方法可能会提高PDAC对免疫治疗的敏感性。
