Department of Urology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Urology, The Third Affiliated Hospital of the Second Military Medical University, Shanghai, China.
J Immunother Cancer. 2024 Jun 21;12(6):e008613. doi: 10.1136/jitc-2023-008613.
Tertiary lymphoid structures (TLSs) serve as organized lymphoid aggregates that influence immune responses within the tumor microenvironment. This study aims to investigate the characteristics and clinical significance of TLSs and tumor-infiltrating lymphocytes (TILs) in clear cell renal cell carcinoma (ccRCC).
TLSs and TILs were analyzed comprehensively in 754 ccRCC patients from 6 academic centers and 532 patients from The Cancer Genome Atlas. Integrated analysis was performed based on single-cell RNA-sequencing datasets from 21 ccRCC patients to investigate TLS heterogeneity in ccRCC. Immunohistochemistry and multiplex immunofluorescence were applied. Cox regression and Kaplan-Meier analyses were used to reveal the prognostic significance.
The study demonstrated the existence of TLSs and TILs heterogeneities in the ccRCC microenvironment. TLSs were identified in 16% of the tumor tissues in 113 patients. High density (>0.6/mm) and maturation of TLSs predicted good overall survival (OS) (p<0.01) in ccRCC patients. However, high infiltration (>151) of scattered TILs was an independent risk factor of poor ccRCC prognosis (HR=14.818, p<0.001). The presence of TLSs was correlated with improved progression-free survival (p=0.002) and responsiveness to therapy (p<0.001). Interestingly, the combination of age and TLSs abundance had an impact on OS (p<0.001). Higher senescence scores were detected in individuals with immature TLSs (p=0.003).
The study revealed the contradictory features of intratumoral TLSs and TILs in the ccRCC microenvironment and their impact on clinical prognosis, suggesting that abundant and mature intratumoral TLSs were associated with decreased risks of postoperative ccRCC relapse and death as well as favorable therapeutic response. Distinct spatial distributions of immune infiltration could reflect effective antitumor or protumor immunity in ccRCC.
三级淋巴结构 (TLS) 作为有组织的淋巴聚集物，影响肿瘤微环境中的免疫反应。本研究旨在探讨 TLS 和肿瘤浸润淋巴细胞 (TIL) 在透明细胞肾细胞癌 (ccRCC) 中的特征和临床意义。
在来自 6 个学术中心的 754 例 ccRCC 患者和来自 The Cancer Genome Atlas 的 532 例患者中全面分析 TLS 和 TIL。基于 21 例 ccRCC 患者的单细胞 RNA 测序数据集进行综合分析，以研究 ccRCC 中 TLS 的异质性。应用免疫组织化学和多重免疫荧光染色。采用 Cox 回归和 Kaplan-Meier 分析揭示预后意义。
本研究表明 ccRCC 微环境中存在 TLS 和 TIL 异质性。在 113 例患者的 16%肿瘤组织中发现了 TLS。TLS 密度高（>0.6/mm）和成熟度预示着 ccRCC 患者的总体生存（OS）良好（p<0.01）。然而，散在 TIL 高浸润（>151）是 ccRCC 预后不良的独立危险因素（HR=14.818，p<0.001）。TLS 的存在与无进展生存期（p=0.002）和对治疗的反应性（p<0.001）的改善相关。有趣的是，年龄和 TLS 丰度的组合对 OS 有影响（p<0.001）。在不成熟的 TLS 个体中检测到更高的衰老评分（p=0.003）。
本研究揭示了 ccRCC 微环境中肿瘤内 TLS 和 TIL 的矛盾特征及其对临床预后的影响，表明丰富和成熟的肿瘤内 TLS 与术后 ccRCC 复发和死亡风险降低以及治疗反应良好相关。免疫浸润的不同空间分布可以反映 ccRCC 中的有效抗肿瘤或促肿瘤免疫。
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