Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-003883.
The aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer.
We performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens.
Varying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer.
The immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.
本研究旨在（1）阐明三级淋巴结构（TLS）状态对人肾透明细胞癌（ccRCC）结局和免疫基因组谱的影响，（2）确定不同泌尿生殖系统癌症（即尿ccRCC 和膀胱癌）中 TLS 的表型差异。
我们对 ccRCC 组织微阵列进行了定量免疫组织化学分析，并通过下一代测序和甲基化阵列分析进行了综合基因组突变分析。由于 ccRCC 的肿瘤免疫微环境通常与其他癌症类型不同，因此我们分析了 ccRCC 与内部膀胱癌标本中 TLS 的表型差异。
在整个 ccRCC 肿瘤中观察到 TLS 的分布模式各不相同，表明 TLS 的存在与预后不良有关。基于 ccRCC 中 TLS 状态的基因组改变分析表明，PI3K-mTOR 通路的改变在 TLS 阳性肿瘤中非常普遍。DNA 甲基化分析还揭示了具有不同 TLS 状态的 ccRCC 样本之间存在明显不同的甲基化特征。然而，ccRCC 和膀胱癌的 TLS 特征明显不同：TLS 对膀胱癌的预后影响与 ccRCC 完全相反。两种癌症类型的 TLS 特征明显不同；TLS 在膀胱癌中更为成熟，具有滤泡样生发中心组织，并且可能在肿瘤内部观察到。CD8、FOXP3、PD-1 和 PD-L1 的标记显示 TLS 周围免疫微环境的多样性存在显著差异。膀胱癌中 TLS 周围的 CD8+、FOXP3+ 和 PD-L1+细胞比例明显高于 ccRCC 中的 TLS；相反，ccRCC 中 TLS 周围的 PD-1+细胞比例明显高于膀胱癌中的 TLS。
ccRCC 的免疫生物学是独特的，并且各种癌症现象与其他癌症类型所见的现象相冲突；因此，比较 ccRCC 和膀胱癌之间的 TLS 特征可能有助于揭示两种癌症之间 TLS 的预后影响、成熟度和空间分布以及 TLS 周围免疫环境的差异。
