Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
World J Urol. 2022 Nov;40(11):2817-2824. doi: 10.1007/s00345-022-04170-5. Epub 2022 Oct 7.
While immunotherapy has shown potent efficacy in clinical practices, patient selection to receive checkpoint blockade is still challenging in prostate cancer (PCa). LAT and ZAP70 functions in lymphocyte activation and plays a critical role in T cell receptor (TCR) signal transduction. However, PCa genomic and clinical data regarding the role of LAT and ZAP70 are limited. We aim to identify and characterize LAT/ZAP70 defined subtypes of PCa.
We elaborated the TCGA PCa data and metastatic castration-resistant prostate cancer (mCRPC) RNA-seq data bioinformatic analysis and systematically elucidated the role of intra-tumoral expressed LAT and ZAP70 in the progression-free survival and immunotherapeutic-related signals. LAT/ZAP70-associated immune infiltration was evaluated using bioinformatic tools. Immunohistochemical staining of serial sections was used to confirm the expression and distribution of LAT, ZAP70 and androgen receptor (AR) in PCa tissues.
Specifically, LAT and ZAP70 revealed increased expressions in PCa when compared to normal tissues and positively associated with intra-tumoral immune cells infiltration. LAT/ZAP70 defined immune-high early-stage PCa revealed higher TP53 mutation frequency and poor prognosis. Transcriptome analysis indicated immune-related signals and CTLA4 expression were highly enhanced in immune-high PCa parallel with higher protein level of MYC and lower AR expression. In mCRPC, LAT/ZAP70 defined immune-high patients also revealed upregulated immune related signals, higher CTLA4 expression and DNA repair deficiency.
LAT/ZAP70 defined immune-high PCa linked to immune infiltration and predicts poor prognosis. Immune-high PCa may receive effective response from immune checkpoint inhibitor parallel with systemic treatment.
免疫疗法在临床实践中已显示出强大的疗效，但在前列腺癌（PCa）中，选择接受检查点阻断治疗的患者仍然具有挑战性。Lat 和 Zap70 在淋巴细胞激活中起作用，并在 T 细胞受体（TCR）信号转导中起关键作用。然而，关于 Lat 和 Zap70 在前列腺癌中的作用的基因组和临床数据有限。我们旨在确定并描述 Lat/Zap70 定义的前列腺癌亚型。
我们详细阐述了 TCGA 前列腺癌数据和转移性去势抵抗性前列腺癌（mCRPC）RNA-seq 数据的生物信息学分析，并系统地阐明了肿瘤内表达的 Lat 和 Zap70 在无进展生存期和免疫治疗相关信号中的作用。使用生物信息学工具评估了 Lat/Zap70 相关免疫浸润。使用连续切片的免疫组织化学染色来确认前列腺癌组织中 Lat、Zap70 和雄激素受体（AR）的表达和分布。
具体而言，与正常组织相比，Lat 和 Zap70 在前列腺癌中表达增加，并与肿瘤内免疫细胞浸润呈正相关。Lat/Zap70 定义的免疫高早期前列腺癌显示出更高的 TP53 突变频率和不良预后。转录组分析表明，免疫相关信号和 CTLA4 表达在免疫高前列腺癌中高度增强，同时伴有 MYC 蛋白水平升高和 AR 表达降低。在 mCRPC 中，Lat/Zap70 定义的免疫高患者也显示出上调的免疫相关信号、更高的 CTLA4 表达和 DNA 修复缺陷。
Lat/Zap70 定义的免疫高前列腺癌与免疫浸润有关，并预示着不良预后。免疫高前列腺癌可能会对免疫检查点抑制剂产生有效的反应，同时进行系统治疗。
