Vaccaro, A.; Yang, F.; van de Walle, T.; Franke, S.; Lugano, R.; Denes, A.; Magoulopoulou, A.; Cid-Farina, I.; Smits, A.; Uhrbom, L.; Libard, S.; Latini, F.; Essand, M.; Nilsson, M.; He, L.; Olsson Bontell, T.; Jakola, A. S.; Ramachandran, M.; Dimberg, A.

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates associated with improved prognosis in numerous tumors. To date, their prognostic value in central nervous system cancers and the events underlying their formation remain unclear. Here, we find that TLS correlate with improved survival in glioblastoma patients. Furthermore, combining spatial transcriptomics of human tissues with longitudinal studies in murine glioma, we establish that the assembly of T cell-rich clusters is a prerequisite for the development of canonical TLS, and show that CD4 T cells play a central role in this process. Indeed, we provide evidence that IL7R+CCR7+ Th1 lymphocytes with lymphoid tissue-inducing potential are recruited to TLS nucleation sites, where they can initiate TLS assembly by expressing lymphotoxin {beta}. Our work defines TLS as a potential prognostic factor in glioblastoma and identifies cellular and molecular mechanisms of TLS formation. These findings have broader implications for the development of TLS-inducing therapies for cancer.