背景:NOD-,含有LRR和pyrin结构域的3(NLRP3)炎性体是先天免疫系统的关键组成部分。众所周知,它在乳腺癌患者的癌变和预后中起着重要作用。虽然NLRP3炎性体激活与长期生存之间关系的临床证据仍然有限,乳腺癌组织的实质细胞或免疫基质细胞在这种癌的发生和进展中的可能作用仍有待阐明.这项研究是对先前临床试验中接受乳腺癌手术的患者的分析。
方法:采用免疫组织化学(IHC)检测NLRP3炎性体通路相关蛋白的表达水平,包括NLRP3,caspase-1,凋亡相关斑点样蛋白(ASC),IL-1β,与邻近正常组织相比,乳腺癌组织的实质和免疫基质细胞中的IL-18,分别。NLRP3炎性体表达与临床病理特征的关系,以及5年生存率使用卡方检验进行分析,Kaplan-Meier存活曲线,和Cox回归分析。
结果:在实质细胞中,与癌旁正常组织相比,乳腺癌组织中ASC和IL-18蛋白水平显著上调(P<0.05)。在免疫基质细胞中,与癌旁正常组织相比,乳腺癌组织中5种NLRP3炎性体通路相关蛋白均显著升高(P<0.05)。发现癌细胞栓子与肿瘤实质细胞中NLRP3的高表达显着相关(x2=4.592,P=0.032),caspase-1的表达与肿瘤进展呈负相关。发现组织学分级与肿瘤免疫基质细胞中IL-18的表达呈正相关(x2=14.808,P=0.001)。Kaplan-Meier生存分析显示,免疫基质细胞中IL-18的高表达和癌细胞栓子的阳性表达均与不良生存有关(P<0.05)。多变量Cox比例风险回归模型提示IL-18高表达和癌细胞栓子阳性是预后不良的独立危险因素。
结论:在先天免疫系统的免疫基质细胞和肿瘤实质细胞中,NLRP3炎性体通路的激活不是各向同性的,在乳腺癌患者中主要功能有所不同。肿瘤实质细胞中的Caspase-1与肿瘤进展呈负相关,乳腺癌组织免疫基质细胞中IL-18的上调是一个有前景的预后生物标志物和潜在的免疫治疗靶点。
背景:该临床试验已在Chictr.org注册。cn注册系统于2018年8月21日(ChiCTR1800017910)。
BACKGROUND: The NOD-, LRR- and pyrin domain‑containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. It has been known to play an important role in the carcinogenesis and prognosis of breast cancer patients. While the clinical evidence of the relationship between NLRP3 inflammasome activation and long-term survival is still limited, the possible roles of parenchymal or immune-stromal cells of breast cancer tissues in contributing to such carcinogenesis and progression still need to be clarified. This study is an analysis of patients receiving breast cancer surgery in a previous clinical trial.
METHODS: Immunohistochemistry (IHC) was used to detect the expression levels of NLRP3 inflammasome pathway-related proteins, including NLRP3, caspase-1, apoptosis-associated speck-like protein (
ASC), IL-1β, and IL-18, in parenchymal and immune-stromal cells of breast cancer tissues compared to those of adjacent normal tissues, respectively. The relationship between NLRP3 inflammasome expression and clinicopathological characteristics, as well as 5-year survivals were analyzed using the Chi-square test, Kaplan-Meier survival curves, and Cox regression analysis.
RESULTS: In the parenchymal cells,
ASC and IL-18 protein levels were significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (P<0.05). In the immune-stromal cells, all the five NLRP3 inflammasome pathway-related proteins were significantly elevated in breast cancer tissues compared with adjacent normal tissues (P < 0.05). Carcinoma cell embolus was found to significantly correlate with high NLRP3 expression in parenchymal cells of the tumor (x2=4.592, P=0.032), while the expression of caspase-1 was negatively correlated with tumor progression. Histological grades were found to have a positive correlation with IL-18 expression in immune-stromal cells of the tumor (x2=14.808, P=0.001). Kaplan-Meier survival analysis revealed that high IL-18 expression in the immune-stromal cells and the positive carcinoma cell embolus were both associated with poor survival (P < 0.05). The multivariable Cox proportional hazards regression model implied that the high IL-18 expression and positive carcinoma cell embolus were both independent risk factors for unfavorable prognosis.
CONCLUSIONS: The activation of NLRP3 inflammasome pathways in immune-stromal and tumor parenchymal cells in the innate immune system was not isotropic and the main functions are somewhat different in breast cancer patients. Caspase-1 in parenchymal cells of the tumor was negatively correlated with tumor progression, and upregulation of IL-18 in immune-stromal cells of breast cancer tissues is a promising prognostic biomarker and a potential immunotherapy target.
BACKGROUND: This clinical trial has been registered at the Chictr.org.cn registry system on 21/08/2018 (ChiCTR1800017910).