The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure
The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure
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DOI：
10.1016/j.urolonc.2013.10.012
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发表时间：
2014-05-01
影响因子：
2.7
通讯作者：
Santos, Lticio
中科院分区：
文献类型：
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作者：
Lima, Luis;Oliveira, Daniela;Santos, Lticio
目的：卡介苗（BCG）免疫疗法是具有中/高复发或进展风险的浅表性膀胱肿瘤的金标准治疗。然而，大约30%的患者对治疗没有反应。有效的BCG治疗需要精确激活1型辅助细胞免疫途径。肿瘤相关巨噬细胞（TAM）通常呈现免疫调节M2表型，并可能直接干扰BCG诱导的抗肿瘤免疫应答。因此，我们的目的是澄清TAM的影响，特别是在基质和肿瘤领域的M2表型，在BCG治疗outcome.Patients和方法：该研究包括99例膀胱癌与BCG治疗。使用CD 68和CD 163抗原的免疫组织化学评价治疗前切除的肿瘤，其分别鉴定谱系巨噬细胞标志物和M2极化特异性细胞表面受体。在间质和肿瘤区域内评估CD 68（+）和CD 163（+）巨噬细胞，并选择高密度浸润细胞点进行计数。缺氧，一个已知的事件，调节巨噬细胞表型，也通过缺氧诱导因子（HEF）-1 α expression.Results：BCG失败的患者有高基质占主导地位的CD 163（+）巨噬细胞计数（高基质，但低肿瘤CD 163（+）巨噬细胞计数）相比，与成功的治疗（71%比47%，P = 0.017）。此外，在单变量分析中观察到，呈现这种表型的患者显示无复发生存率降低（对数秩，P = 0.008），BCG治疗失败的风险明显增加2倍（风险比= 2.343; 95%CI：1.197-4.587; P = 0.013）。即使调整了潜在的混杂因素，如年龄和治疗方案，多变量分析显示复发风险增加2.6倍（风险比= 2.627; 95%CI：1.340-5.150; P = 0.005）。高基质CD 163（+）巨噬细胞计数也与肿瘤区域中HIF-1 α的低表达相关，而肿瘤中高计数的CD 163（+）表示肿瘤巢中HIF-1 α的高表达。此外，CD 163（+）巨噬细胞浸润增加，主要在间质区域，而不是在肿瘤中，可能是BCG治疗结果的有用指标，可能是由于其免疫抑制表型。(C)2014爱思唯尔公司All rights reserved.
Objective: Bacillus Calmette-Guerin (BCG) immunotherapy is the gold standard treatment for superficial bladder tumors with intermediate/high risk of recurrence or progression. However, approximately 30% of patients fail to respond to the treatment. Effective BCG therapy needs precise activation of the type 1 helper cells immune pathway. Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype and may directly interfere with the BCG-induced antitumor immune response. Thus, we aim to clarify the influence of TAMs, in particular of the M2 phenotype in stroma and tumor areas, in BCG treatment outcome.Patients and methods: The study included 99 patients with bladder cancer treated with BCG. Tumors resected before treatment were evaluated using immunohistochemistry for CD68 and CD 163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. CD68(+) and CD163(+) macrophages were evaluated within the stroma and tumor areas, and high density of infiltrating cells spots were selected for counting. Hypoxia, an event known to modulate macrophage phenotype, was also assessed through hypoxia induced factor (HEF)-1 alpha expression.Results: Patients in whom BCG failed had high stroma-predominant CD163(+) macrophage counts (high stroma but low tumor CD163(+) macrophages counts) when compared with the ones with a successful treatment (71% vs. 47%, P = 0.017). Furthermore, patients presenting this phenotype showed decreased recurrence-free survival (log rank, P = 0.008) and a clear 2-fold increased risk of BCG treatment failure was observed in univariate analysis (hazard ratio = 2.343; 95% CI: 1.197-4.587; P = 0.013). Even when adjusted for potential confounders, such as age and therapeutic scheme, multivariate analysis revealed 2.6-fold increased risk of recurrence (hazard ratio = 2.627; 95% CI: 1.340-5.150; P = 0.005). High stroma-predominant CD163(+) macrophage counts were also associated with low expression of HIF-1 alpha in tumor areas, whereas high counts of CD163(+) in the tumor presented high expression of HIF-1 alpha in tumor nests.Conclusions: TAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163(+) macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype. (C) 2014 Elsevier Inc. All rights reserved.