Lee Chin-Cheng, Ho Kuo-Hao, Huang Tzu-Wen, Shih Chwen-Ming, Hsu Shao-Yuan, Liu Ann-Jeng, Chen Ku-Chung
Department of Pathology and Laboratory Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan; Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Life Sci. 2021 Jul 15;277:119438. doi: 10.1016/j.lfs.2021.119438. Epub 2021 Mar 30.
Immune checkpoints regulate immunity to prevent autoimmunity and protect the host from damage during pathogenic infection. They also participate in subverting immune surveillance and promote antitumor immunity in cancers. Although immunotherapy improves clinical outcomes, not all cancer patients experience expected responses after therapy. Hence, it would be meaningful to explore crucial immune checkpoints in cancers for future immunotherapies.
By analyzing pan-cancer data in The Cancer Genome Atlas (TCGA), cluster of differentiation 276 (CD276), also known as B7H3, was found to be a risk gene in several cancers. A positive correlation existed between CD276 and natural killer (NK) cell infiltration. Overexpression of CD276 attenuated NK cell-mediated cell killing. Furthermore, CD276 levels showed a significant negative association with microRNA (miR)-29c-3p. Overexpression of miR-29c-3p rescued CD276-reduced NK cell cytotoxicity. According to gene set enrichment analyses, CD276-associated genes were found to be enriched in genes that targeted Myc. A negative correlation existed between miR-29 expression and Myc activity. CD276 enhanced Myc phosphorylation levels while suppressing miR-29c-3p expression. In contrast, miR-29c-3p inhibited CD276 expression, leading to reduced Myc activity. Myc suppressed miR-29c-3p expression while promoting CD276 upregulation.
These findings suggest that a negative regulatory loop among CD276, Myc, and miR-29c-3p influences cancer cells against NK cell cytotoxicity.
免疫检查点调节免疫以预防自身免疫，并在病原体感染期间保护宿主免受损伤。它们还参与颠覆免疫监视并促进癌症中的抗肿瘤免疫。尽管免疫疗法改善了临床结果，但并非所有癌症患者在治疗后都能获得预期反应。因此，探索癌症中的关键免疫检查点以用于未来的免疫疗法具有重要意义。
通过分析癌症基因组图谱（TCGA）中的泛癌数据，发现分化簇276（CD276），也称为B7H3，是几种癌症中的一个风险基因。CD276与自然杀伤（NK）细胞浸润之间存在正相关。CD276的过表达减弱了NK细胞介导的细胞杀伤作用。此外，CD276水平与微小RNA（miR）-29c-3p呈显著负相关。miR-29c-3p的过表达挽救了CD276降低的NK细胞细胞毒性。根据基因集富集分析，发现与CD276相关的基因在靶向Myc的基因中富集。miR-29表达与Myc活性之间存在负相关。CD276增强Myc磷酸化水平，同时抑制miR-29c-3p表达。相反，miR-29c-3p抑制CD276表达，导致Myc活性降低。Myc抑制miR-29c-3p表达，同时促进CD276上调。
这些发现表明，CD276、Myc和miR-29c-3p之间的负调控环影响癌细胞抵抗NK细胞的细胞毒性。
