WNT /beta-catenin 通路信号在大多数实体肿瘤中被激活
WNT/beta-catenin Pathway Signaling Activated in Most Solid Tumors
大多数人类实体肿瘤,包括结肠癌、肾脏、肺肿瘤与WNT /β-catenin通路信号被激活与T细胞排斥有关。
芝加哥——在大多数人类实体肿瘤,包括结肠癌、肾、肺肿瘤,WNT /β-catenin通路信号被激活与T细胞排斥，据一项研究在2016年美国临床肿瘤学会(ASCO)年度Meeting.1
“T细胞感染的肿瘤微环境以免疫抑制通路的表达为特征，并预测患者对免疫治疗的结果，”首席研究员、芝加哥大学医学助理教授、医学肿瘤学家Jason J. Luke博士说。
为了更好地理解在实体肿瘤没有T细胞反应的分子机制基础,调查人员评估WNT /β-catenin通路的作用。
“β-catenin压制CCL4,导致缺乏Batf3 +招募,T细胞启动失败,和检查点封锁的反应缺失,”卢克博士指出。
在这项研究中，研究人员从癌症基因组图谱(TCGA)中收集基因表达数据，并使用T细胞炎症的基因表达特征来分离数据，以通过免疫表型识别患者样本。然后他们发现基因表达变化将触发β-catenin信号通路和对肿瘤进行免疫组织化学样品来确定一个相关性的存在核β-catenin和T细胞渗透存在的缺乏。
结果显示，在13种肿瘤组织学中，CTNNB1的激活突变或Axin1、Axin2、APC1、APC2的失活突变均在食管肿瘤的9%至结肠肿瘤的67%范围内观察到。
研究人员还发现了12个进一步组织学窝藏高架β-catenin通路的表达元素,包括WNT配体。
只有3种肿瘤类型，胰腺、甲状腺和副神经节瘤，没有表现出与免疫特征缺失相关的激活。
WNT/beta-catenin Pathway Signaling Activated in Most Solid Tumors
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WNT/β-catenin pathway signaling is associated with T cell exclusion and is activated in most human solid tumors, including colon, kidney, and lung tumors.
WNT/β-catenin pathway signaling is associated with T cell exclusion and is activated in most human solid tumors, including colon, kidney, and lung tumors.
CHICAGO — WNT/β-catenin pathway signaling is associated with T cell exclusion and is activated in most human solid tumors, including colon, kidney, and lung tumors, according to a study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting.1
"The T cell-inflamed tumor microenvironment is characterized by expression of immune-inhibitory pathways and predicts patient outcomes to immunotherapy," said lead investigator Jason J. Luke, MD, assistant professor of medicine and medical oncologist at The University of Chicago Medicine.
To better understand the molecular mechanisms underpinning the absence of a T cell response in solid tumors, investigators assessed the role of the WNT/β-catenin pathway.
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"β-catenin represses CCL4, leading to a lack of Batf3+ recruitment, failed T cell priming, and non-response to checkpoint blockade," Dr Luke noted.
For the study, researchers collected gene expression data from The Cancer Genome Atlas (TCGA) and segregated the data using a T cell-inflamed gene expression signature to identify patient samples by immune phenotype. They then identified gene expression changes predicted to trigger the β-catenin signaling pathway and performed immunohistochemistry on tumor samples to determine if a correlation between the presence of nuclear β-catenin and the lack of a T cell infiltrate exists.
Results showed that predicted activating mutations in CTNNB1 or inactivating mutations in Axin1, Axin2, APC1, and APC2 were observed within 13 tumor histologies ranging in frequency from 9% in esophageal tumors to 67% in colon tumors.
Researchers also identified 12 further histologies harboring elevated expression of β-catenin pathway elements, including WNT ligands. Only 3 tumor types, pancreatic, thyroid, and paraganglioma, did not exhibit activation that was associated with absence of immune signatures.
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Immunohistochemistry further demonstrates an inverse correlation between β-catenin and CD8+ T cells.
"Activation of WNT/β-catenin signaling likely contributes to the non-T cell-inflamed phenotype across many cancers," Dr Luke concluded. "β-catenin as a mediator of immune exclusion may represent a rational therapeutic target for combination immunotherapy."
Reference
Luke JJ, Bao R, Spranger S, et al. Correlation of WNT/β-catenin pathway activation with immune exclusion across most human cancers. J Clin Oncol. 2016; 34 (suppl; abstr 3004).
