Shen Shaoping, Cui Yong, Li Mingxiao, Yu Kefu, Zhu Qinghui, Zhang Xiaokang, Shen Weicheng, Li Haoyi, Jiang Haihui, Li Ming, Wang Xijie, Zhao Xuzhe, Ren Xiaohui, Lin Song
National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Neuro Oncol. 2025 Jan 12;27(1):140-154. doi: 10.1093/neuonc/noae167.
Glioma, characterized by limited lymphocytic infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study aims to explore therapeutic strategies for inducing tertiary lymphoid structure (TLS) formation within the glioma microenvironment (GME) to transition it from an immune resistant to an activated state.
TLS formation in GME was successfully induced by intracranial administration of Toll-like receptor (TLR) agonists (OK-432, TLR2/4/9 agonist) and glioma antigens (i.c. αTLR-mix). We employed staining analysis, antibody neutralization, single-cell RNA sequencing (scRNA-Seq), and BCR/TCR sequencing to investigate the underlying mechanisms of TLS formation and its role in anti-glioma immunity. Additionally, a preliminary translational clinical study was conducted.
TLS formation correlated with increased lymphocyte infiltration in GME and led to improved prognosis in glioma-bearing mice. In the study of TLS induction mechanisms, certain macrophages/microglia and Th17 displayed markers of "LTo" and "LTi" cells, respectively, interaction through LTα/β-LTβR promoted TLS induction. Post-TLS formation, CD4 + and CD8 + T cells but not CD19 + B cells contributed to anti-glioma immunity. Comparative analysis of B/T cells between brain and lymph node showed that brain B/T cells unveiled the switch from naïve to mature, some B cells highlighted an enrichment of class switch recombination (CSR)-associated genes, V gene usage, and clonotype bias were observed. In related clinical studies, i.c. αTLR-mix treatment exhibited tolerability, and chemokines/cytokines assay provided preliminary evidence supporting TLS formation in GME.
TLS induction in GME enhanced anti-glioma immunity, improved the immune microenvironment, and controlled glioma growth, suggesting potential therapeutic avenues for treating glioma in the future.
胶质瘤以淋巴细胞浸润有限为特征，是一种对各种免疫疗法不敏感的“免疫荒漠”肿瘤。本研究旨在探索诱导胶质瘤微环境（GME）内三级淋巴结构（TLS）形成的治疗策略，使其从免疫抵抗状态转变为激活状态。
通过颅内给予Toll样受体（TLR）激动剂（OK-432，TLR2/4/9激动剂）和胶质瘤抗原（颅内αTLR混合物）成功诱导GME中TLS形成。我们采用染色分析、抗体中和、单细胞RNA测序（scRNA-Seq）和BCR/TCR测序来研究TLS形成的潜在机制及其在抗胶质瘤免疫中的作用。此外，还进行了一项初步的转化临床研究。
TLS形成与GME中淋巴细胞浸润增加相关，并改善了荷瘤小鼠的预后。在TLS诱导机制研究中，某些巨噬细胞/小胶质细胞和Th17分别显示出“LTo”和“LTi”细胞的标志物，通过LTα/β-LTβR相互作用促进了TLS诱导。TLS形成后，CD4 +和CD8 + T细胞而非CD19 + B细胞有助于抗胶质瘤免疫。脑与淋巴结中B/T细胞的比较分析表明，脑B/T细胞显示出从幼稚到成熟的转变，一些B细胞突出显示了类别转换重组（CSR）相关基因的富集，观察到V基因使用和克隆型偏向。在相关临床研究中，颅内αTLR混合物治疗表现出耐受性，趋化因子/细胞因子检测提供了支持GME中TLS形成的初步证据。
GME中TLS诱导增强了抗胶质瘤免疫，改善了免疫微环境并控制了胶质瘤生长，提示未来治疗胶质瘤的潜在途径。
