肿瘤细胞治疗研究
英文原题：Toll-like receptor agonists promote the formation of tertiary lymphoid structure and improve anti-glioma immunity.
GME中TLS的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治疗途径。
胶质瘤以淋巴细胞浸润有限为特征，构成一种“免疫荒漠”型肿瘤，对多种免疫治疗不敏感。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，以使其从免疫抵抗状态转变为激活状态。
GME中TLS的形成通过颅内给予Toll样受体（TLR）激动剂（OK-432，TLR2/4/9激动剂）和胶质瘤抗原（i.c. αTLR-mix）成功诱导。我们采用染色分析、抗体中和、单细胞RNA测序（scRNA-Seq）以及BCR/TCR测序来探究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，并导致荷胶质瘤小鼠预后改善。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“LTo”和“LTi”细胞标志物，通过LTα/β-LTβR相互作用促进TLS诱导。TLS形成后，CD4+和CD8+T细胞而非CD19+B细胞参与抗胶质瘤免疫。脑与淋巴结之间B/T细胞的比较分析显示，脑B/T细胞揭示了从初始到成熟的转换，一些B细胞突出显示类别转换重组（CSR）相关基因的富集，观察到V基因使用和克隆型偏倚。在相关临床研究中，i.c. αTLR-mix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。
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
MEMBER ACCOUNT
登录成功会直接打开下一页。
