CTNNB1 mutation suppresses infiltration of immune cells in hepatocellular carcinoma through miRNA-mediated regulation of chemokine expression
CTNNB1 mutation suppresses infiltration of immune cells in hepatocellular carcinoma through miRNA-mediated regulation of chemokine expression
复制标题
CTNNB1 突变通过 miRNA 介导的趋化因子表达调节抑制肝细胞癌中免疫细胞的浸润。
DOI：
10.1016/j.intimp.2020.107043
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发表时间：
2020-12-01
影响因子：
5.6
通讯作者：
Tu, Kangsheng
中科院分区：
文献类型：
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作者：
Xiao, Xuelian;Mo, Huanye;Tu, Kangsheng
肝细胞癌（HCC）中CTNNB 1基因突变与免疫排斥相关，CTNNB 1突变的HCC患者往往主要对抗PD 1治疗耐药。然而，缺乏对CTNNB 1突变型HCC中免疫细胞浸润的系统评价，CTNNB 1突变导致的免疫排斥机制仍不清楚。基于CTNNB 1在HCC中的突变状态，我们研究了RNA和miRNA的表达以及免疫细胞的浸润。从TCGA下载的数据显示，CTNNB 1突变的HCC具有CTNNB 1的表达增加。CTNNB 1突变的HCC显示浸润评分降低以及某些类型的免疫细胞的丰度，包括CD 4初始T细胞、CD 4 + T细胞、Tex细胞、Th 2细胞、Tfh细胞、B细胞、巨噬细胞和NK细胞。此外，有13个趋化因子中的所有14个差异表达的趋化因子（DE-CKs）在CTNNB 1突变体相比，在野生型下调。DE-CKs的表达与浸润评分及B细胞、CD 8+细胞、CD 4+细胞、巨噬细胞、中性粒细胞、树突状细胞6种免疫细胞浸润水平呈正相关。此外，302个差异表达的免疫相关基因（DE-IRGs）主要参与人体免疫应答和细胞因子受体相互作用。鉴定差异表达的miRNAs（DE-miRNAs）的靶DE-IRGs，并将其用于构建DE-miRNAs和DE-CKs的网络。总的来说，CTNNB 1突变在HCC中导致趋化因子表达减少，随后部分通过调节特定的miRNA-IRG-CK轴抑制免疫细胞浸润，这表明Wnt/f3-catenin信号传导干扰与CTNNB 1突变HCC中的免疫治疗的潜在组合。
Mutations in the CTNNB1 gene in hepatocellular carcinoma (HCC) are related to immune exclusion, and HCC patients with CTNNB1 mutations tend to be primarily resistant to anti-PD1 therapy. However, systemic evaluation of immune cell infiltration in HCC with mutant CTNNB1 is lacking, and the mechanism of immune exclusion resulting from CTNNB1 mutations remains unclear. Based on CTNNB1 mutation status in HCC, we investigated RNA and miRNA expression and infiltration of immune cells. Data downloaded from TCGA showed that HCC with CTNNB1 mutation had an increased expression of CTNNB1. HCC with CTNNB1 mutation showed a reduction in infiltration score as well as in abundance of certain kinds of immune cells, including CD4 naive T cells, CD4+ T cells, Tex cells, Th2 cells, Tfh cells, B cells, macrophages, and NK cells. Furthermore, there were 13 chemokines downregulated among all the 14 differentially expressed chemokines (DE-CKs) in CTNNB1 mutants compared to those in the wild type. A positive correlation was found between the expression of DE-CKs and infiltration score, as well as infiltration level of 6 types of immune cells, namely B cells, CD8+ cells, CD4+ cells, macrophages, neutrophils, and dendritic cells. Additionally, 302 differentially expressed immune-related genes (DE-IRGs) were involved mainly in the human immune response and cytokine-cytokine receptor interaction. The target DE-IRGs of differentially expressed miRNAs (DE-miRNAs) were identified and used to construct a network with DE-miRNAs and DE-CKs. Overall, CTNNB1 mutation in HCC led to a decrease in chemokine expression and subsequent suppression of immune cell infiltration partly through regulating specific miRNA-IRG-CK axes, pointing to a potential combination of interference of Wnt/f3-catenin signaling with immunotherapy in HCC with CTNNB1 mutation.