Cakmak Pinar, Lun Jennifer H, Singh Aakanksha, Macas Jadranka, Schupp Jonathan, Schuck Jonas, Mahmoud Zeina, Köhler Miriam, Starzetz Tatjana, Burger Michael C, Steidl Eike, Hasse Lucie Marie, Hattingen Elke, Plate Karl H, Reiss Yvonne, Imkeller Katharina
Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany; Frankfurt Cancer Institute (FCI), Frankfurt, Germany.
Goethe University, University Hospital, Institute of Neurology (Edinger Institute), Frankfurt, Germany; Frankfurt Cancer Institute (FCI), Frankfurt, Germany; University Cancer Center (UCT), Frankfurt, Germany.
Immunity. 2025 Nov 11;58(11):2847-2863.e8. doi: 10.1016/j.immuni.2025.09.018. Epub 2025 Oct 21.
Adult-type diffuse gliomas, the most common primary brain tumors, respond poorly to immune-based therapies and are considered immunologically "cold" tumors. Here, we examined the features and clinical relevance of glioma intratumoral tertiary lymphoid structures (TLSs) using spatial transcriptome and proteome profiling. In a cohort of 642 gliomas, TLSs were present in 15% of tumors and associated with a remodeled perivascular space and spatial redistribution of extracellular matrix components. Three distinct TLS subtypes could be defined based on differing cellular composition and immune activity. While all subtypes lacked classical germinal center architecture, certain TLSs exhibited features of dynamic immune functions, including clonal T and B cell expansion, generation of IgA⁺ and IgG⁺ plasma cells, and dendritic cell-T cell interactions. The presence of TLSs with active immune response features correlated with improved overall survival. Thus, a functional adaptive immune response is detectable in some gliomas, with implications for stratification and treatment.
成人型弥漫性胶质瘤是最常见的原发性脑肿瘤，对基于免疫的疗法反应不佳，被认为是免疫“冷”肿瘤。在这里，我们使用空间转录组和蛋白质组分析方法研究了胶质瘤瘤内三级淋巴结构（TLSs）的特征及其临床相关性。在一个包含642例胶质瘤的队列中，15%的肿瘤存在TLSs，且与重塑的血管周围间隙和细胞外基质成分的空间重新分布相关。根据不同的细胞组成和免疫活性可定义三种不同的TLS亚型。虽然所有亚型都缺乏经典的生发中心结构，但某些TLSs表现出动态免疫功能的特征，包括克隆性T细胞和B细胞扩增、IgA⁺和IgG⁺浆细胞的产生以及树突状细胞与T细胞的相互作用。具有活跃免疫反应特征的TLSs的存在与总体生存率的提高相关。因此，在一些胶质瘤中可检测到功能性适应性免疫反应，这对分层和治疗具有重要意义。
