Spatial and maturity heterogeneity of tertiary lymphoid structures shapes immune microenvironment and progression in prostate cancer

IF 9.4 Q1 ONCOLOGY
Zhongyuan Wang , Qintao Ge , Ren Mo , Jiahe Lu , Xi Tian , Aihetaimujiang Anwaier , Shiqi Ye , Siqi Zhou , Weihang Guo , Chuanhai Cai , Jianfeng Yang , Hailiang Zhang , Xiaojian Qin , Dingwei Ye , Wenhao Xu
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引用次数: 0

Abstract

Background

Tertiary lymphoid structure (TLS), ectopic lymphoid aggregates formed in response to chronic inflammation, have emerged as potential prognostic biomarkers and mediators of anti-tumor immunity in various cancers. However, the heterogeneity of TLS spatial distribution, maturity, and their prognostic and immunological significance in prostate cancer (PCa) remain poorly characterized.

Methods

We utilized immunohistochemistry, multispectral fluorescence immunohistochemistry (mIHC) and spatial multi-omics analyses to evaluate the heterogeneity of TLS and its relationship with immune components in the tumor microenvironment (TME). Prognostic implications were assessed in 701 PCa patients from the TCGA and Fudan University Shanghai Cancer Center cohorts. The association between TLS heterogeneity and immunoreactivity was assessed through the quantification of immune cell infiltration. CellTreck and robust cell type decomposition deconvolution algorithms were used to decipher the colocalization features of each cell, cell-cell communication and ligand-receptor features within TLS regions.

Results

In PCa, TLSs were detected in approximately 20 % of patients across both cohorts, with intratumoral TLS (intra-TLS) being twice as prevalent as peritumoral TLS (peri‑TLS). Patients harboring intra-TLS exhibited significantly longer disease-free and progression-free survival. Compared to peri‑TLS, intra-TLS were more mature, characterized by increased T-effector cell infiltration, activation of interferon pathways, and the presence of follicular dendritic cell centers and B cell aggregates. Notably, compared with immature TLS, mature TLS were markedly associated with reduced PD-L1 expression, lower regulatory T cells (Tregs) infiltration, and increased high endothelial venules (HEVs) density, indicative of an immunologically active microenvironment. Spatial multi-omics analysis revealed that mature TLS exhibited enriched immune cell diversity and HEVs density, suggesting enhanced anti-tumor immunity. Furthermore, cell-cell communication analysis identified significant interactions between CCL5+ dendritic cells and ACKR1+ activated B cells within mature TLS, reflecting the enhanced capacity of mature TLS to orchestrate robust antigen presentation and B-cell-driven immune responses.

Conclusions

In conclusion, this study highlights the prognostic and immunological implications of TLS heterogeneity in PCa, demonstrating that the spatial distribution and maturity of TLSs are closely linked to TME activation and improved clinical outcomes. These findings provide novel insights into the immune landscape of PCa and establish a foundation for immune-based precision stratification and therapeutic development.
三级淋巴结构的空间和成熟度异质性影响前列腺癌的免疫微环境和进展
背景:三级淋巴样结构(TLS)是在慢性炎症反应中形成的异位淋巴样聚集体,已成为各种癌症中潜在的预后生物标志物和抗肿瘤免疫介质。然而,在前列腺癌(PCa)中,TLS的空间分布、成熟度及其预后和免疫学意义的异质性尚不清楚。方法采用免疫组织化学、多光谱荧光免疫组织化学(mIHC)和空间多组学分析,评价肿瘤微环境(TME)中TLS的异质性及其与免疫成分的关系。对来自TCGA和复旦大学上海癌症中心队列的701例PCa患者的预后影响进行了评估。通过免疫细胞浸润定量评估TLS异质性与免疫反应性之间的关系。使用celltrek和鲁棒细胞类型分解反卷积算法来破译TLS区域内每个细胞的共定位特征、细胞-细胞通信和配体-受体特征。结果在PCa中,两个队列中约有20%的患者检测到TLS,其中肿瘤内TLS (intra-TLS)的发生率是肿瘤周围TLS (peri -TLS)的两倍。携带intra-TLS的患者表现出更长的无病和无进展生存期。与TLS周围相比,TLS内更成熟,其特征是t效应细胞浸润增加,干扰素通路激活,滤泡树突状细胞中心和B细胞聚集物的存在。值得注意的是,与未成熟的TLS相比,成熟的TLS与PD-L1表达降低、调节性T细胞(Tregs)浸润降低以及内皮小静脉(HEVs)高密度增加显著相关,表明免疫活性微环境。空间多组学分析显示,成熟的TLS具有丰富的免疫细胞多样性和hev密度,表明其抗肿瘤免疫能力增强。此外,细胞间通讯分析发现,成熟TLS中CCL5+树突状细胞和ACKR1+活化的B细胞之间存在显著的相互作用,反映了成熟TLS协调稳健抗原呈递和B细胞驱动免疫应答的能力增强。总之,本研究强调了TLS异质性在PCa中的预后和免疫学意义,表明TLS的空间分布和成熟度与TME激活和临床预后的改善密切相关。这些发现为PCa的免疫景观提供了新的见解,并为基于免疫的精确分层和治疗开发奠定了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
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