Department of Urology, University of Texas Health San Antonio (UTHSA), San Antonio, Texas, United States.
Department of Molecular Medicine, University of Texas Health San Antonio (UTHSA), San Antonio, Texas, United States.
Cancer Med. 2023 Apr;12(7):8970-8980. doi: 10.1002/cam4.5579. Epub 2022 Dec 29.
Bladder tumor-infiltrating CD56 NK cells are more tumor cytotoxic than their CD56 counterparts. Identification of NK cell subsets is labor-intensive and has limited utility in the clinical setting. Here, we sought to identify a surrogate marker of bladder CD56 NK cells and to test its prognostic significance.
CD56 and CD56 NK cells were characterized with the multiparametric flow (n = 20) and mass cytometry (n = 21) in human bladder tumors. Transcriptome data from bladder tumors (n = 351) profiled by The Cancer Genome Atlas (TCGA) were analyzed. The expression levels of individual markers in intratumoral CD56 and CD56 NK cells were visualized in tSNE plots. Expressions of activation markers were also compared between Killer Cell Lectin-Like Receptor Subfamily F Member 1 (KLRF1) and KLRF1 NK cells.
Intratumoral CD56 NK cells displayed a more activated phenotype compared to the CD56 subset. Multiple intratumoral cell types expressed CD56, including bladder tumor cells and nonspecific intratumoral CD56 expression was associated with worse patient survival. Thus, an alternative to CD56 as a marker of CD56 NK cells was sought. The activation receptor KLRF1 was significantly increased on CD56 but not on CD56 NK cells. Intratumoral KLRF1 NK cells were more activated and expressed higher levels of activation molecules compared with KLRF1 NK cells, analogous to the distinct effector function of NK cells across CD56 expression. High intratumoral KLRF1 was associated with improved recurrence-free survival (hazard ratio [HR] 0.53, p = 0.01), cancer-specific survival (HR 0.47, p = 0.02), and overall survival (HR 0.54, p = 0.02) on multivariable analyses that adjusted for clinical and pathologic variables.
KLRF1 is a promising prognostic marker in bladder cancer and may guide treatment decisions upon validation.
浸润膀胱肿瘤的 CD56 NK 细胞比 CD56 细胞具有更强的肿瘤细胞毒性。NK 细胞亚群的鉴定是一项劳动密集型工作，在临床环境中的应用有限。在这里，我们试图鉴定一种膀胱 CD56NK 细胞的替代标志物，并检验其预后意义。
使用多参数流式细胞术（n=20）和质谱流式细胞术（n=21）对人类膀胱肿瘤中的 CD56 和 CD56 NK 细胞进行了特征分析。分析了癌症基因组图谱（TCGA）对 351 例膀胱肿瘤的转录组数据。在 tSNE 图中可视化了肿瘤内 CD56 和 CD56 NK 细胞中单个标志物的表达水平。还比较了激活标志物在 Killer Cell Lectin-Like Receptor Subfamily F Member 1（KLRF1）和 KLRF1 NK 细胞中的表达。
与 CD56 亚群相比，肿瘤内 CD56 NK 细胞表现出更激活的表型。多种肿瘤内细胞类型表达 CD56，包括膀胱肿瘤细胞，并且非特异性肿瘤内 CD56 表达与患者生存预后较差相关。因此，寻求替代 CD56 作为 CD56 NK 细胞标志物的方法。激活受体 KLRF1 在 CD56 上显著增加，但在 CD56 NK 细胞上则没有。与 KLRF1 NK 细胞相比，肿瘤内 KLRF1 NK 细胞更激活，并且表达更高水平的激活分子，类似于 NK 细胞在 CD56 表达上的不同效应功能。肿瘤内高 KLRF1 与无复发生存（风险比[HR]0.53，p=0.01）、癌症特异性生存（HR0.47，p=0.02）和总生存（HR0.54，p=0.02）显著相关，在多变量分析中调整了临床和病理变量。
KLRF1 是膀胱癌有前途的预后标志物，在验证后可能指导治疗决策。
