Xu Ziang, Zeng Han, Liu Zhaopei, Jin Kaifeng, Chang Yuan, Wang Yiwei, Liu Li, Zhu Yu, Xu Le, Wang Zewei, Guo Jianming, Xu Jiejie
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Urol Oncol. 2022 Mar;40(3):109.e11-109.e20. doi: 10.1016/j.urolonc.2021.08.024. Epub 2021 Sep 30.
In tumor immune microenvironment, the functions of tumor-associated macrophages (TAMs), including phagocytosis and immunomodulatory, have attracted increasing attention recently. With the discovery of CD47-signal regulatory protein-α (SIRPα) as "don't eat me" signaling pathway, the role of novel subpopulation of TAMs expressing SIRPα has not been fully elucidated in a wide spectrum of solid tumors including bladder cancer. In this study, we investigated the prognostic and predictive implication of SIRPα TAMs regarding clinical outcomes and adjuvant chemotherapeutic benefit in muscle-invasive bladder cancer (MIBC), and preliminarily characterized the phenotypic features of SIRPα TAMs and its relationship with immune contexture.
A total of 141 histochemical MIBC samples from Zhongshan Hospital (ZS), 45 fresh tissue samples, and 391 MIBC patients from TCGA database were enrolled in this study. SIRPα TAMs was evaluated by immunohistochemical staining of CD68 and SIRPα, and flow cytometry fluorescence staining.
Our results illustrated that SIRPα TAMs were enriched in MIBC specimens. Patients with high SIRPα TAMs infiltration suffered significant poor overall survival and recurrence-free survival (P = 0.0030 and P = 0.0282). SIRPα TAMs infiltration was an independent prognosticator in multivariate Cox model. Moreover, adjuvant chemotherapy (ACT) application showed significantly survival benefit in patients with low SIRPα TAMs infiltration (P = 0.0135). SIRPα TAMs with suppressive phenotype exhibited a positive correlation with immune tolerance and dysfunctional CD8 T cells in MIBC.
SIRPα TAMs infiltration indicated poor prognosis and ACT resistance in MIBC. Immunosuppressive SIRPα TAMs is closely related to immune evasion with exhausted T cells states, suggesting the prospect of SIRPα TAMs as a potential therapeutic target in MIBC.
在肿瘤免疫微环境中，肿瘤相关巨噬细胞（TAM）的功能，包括吞噬作用和免疫调节作用，近来受到越来越多的关注。随着CD47信号调节蛋白α（SIRPα）作为“别吃我”信号通路的发现，表达SIRPα的新型TAM亚群在包括膀胱癌在内的多种实体瘤中的作用尚未完全阐明。在本研究中，我们调查了SIRPα⁺ TAM对肌层浸润性膀胱癌（MIBC）临床结局和辅助化疗获益的预后及预测意义，并初步表征了SIRPα⁺ TAM的表型特征及其与免疫微环境的关系。
本研究纳入了来自中山医院（ZS）的141份组织化学MIBC样本、45份新鲜组织样本以及来自TCGA数据库的391例MIBC患者。通过CD68和SIRPα的免疫组织化学染色以及流式细胞术荧光染色评估SIRPα⁺ TAM。
我们的结果表明，SIRPα⁺ TAM在MIBC标本中富集。SIRPα⁺ TAM浸润水平高的患者总体生存期和无复发生存期显著较差（P = 0.0030和P = 0.0282）。在多变量Cox模型中，SIRPα⁺ TAM浸润是一个独立的预后因素。此外，辅助化疗（ACT）应用在SIRPα⁺ TAM浸润水平低的患者中显示出显著的生存获益（P = 0.0135）。具有抑制表型的SIRPα⁺ TAM与MIBC中的免疫耐受和功能失调的CD8⁺ T细胞呈正相关。
SIRPα⁺ TAM浸润表明MIBC预后不良且对ACT耐药。免疫抑制性SIRPα⁺ TAM与T细胞耗竭状态下的免疫逃逸密切相关，提示SIRPα⁺ TAM作为MIBC潜在治疗靶点的前景。
