Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Guizhou Medical University, Guiyang, China.
Immune Cells and Antibody Engineering Research Center of Guizhou Province, Key Laboratory of Biology and Medical Engineering, Guizhou Medical University, Guiyang, China.
Cancer Sci. 2023 Jun;114(6):2238-2253. doi: 10.1111/cas.15775. Epub 2023 Mar 17.
Anterior gradient-2 (AGR2) is crucial to breast cancer progression. However, its role in the tumor immune microenvironment remains unclear. RNA sequencing expression profiles and associated clinical information were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases, respectively. The AGR2 expression patterns were verified using clinical samples of breast cancer. Based on single-cell transcriptomic data, AGR2 expression patterns were identified and cell communication analysis was carried out. Furthermore, the roles of AGR2 in breast tumor progression were explored by a series of functional experiments. We found that DNA methylation was an important mechanism for regulating the expression patterns of AGR2. Patients with AGR2 low expression displayed an immune "hot" and immunosuppressive phenotype characterized by high abundance of tumor immune cell infiltration and increased enrichment scores for transforming growth factor-β (TGF-β) and epithelial-mesenchymal transition pathways, whereas patients with AGR2 high expression showed an opposite immunologic feature with a lack of immune cell infiltration, suggestive of an immune "cold" and desert phenotype. Moreover, single-cell analysis further revealed that AGR2 in malignant cells alters cell-cell interactions by coordinating cytokine-chemokine signaling and immune infiltration. Notably, two immunotherapy cohorts revealed that AGR2-coexpressed genes could serve as prognostic indicators of patient survival. In conclusion, AGR2 could promote breast cancer progression by affecting the tumor immune microenvironment. Patients with AGR2 low expression could be suitable for combination treatment with immune checkpoint inhibitor agents and TGF-β blockers. Therefore, this study provides a theoretical foundation for developing a strategy for personalized immunotherapy to patients with breast cancer.
前梯度-2（AGR2）对乳腺癌的进展至关重要。然而，其在肿瘤免疫微环境中的作用尚不清楚。分别从癌症基因组图谱和基因表达综合数据库下载了 AGR2 的 RNA 测序表达谱和相关临床信息。使用乳腺癌的临床样本验证了 AGR2 的表达模式。基于单细胞转录组学数据，鉴定了 AGR2 的表达模式，并进行了细胞通讯分析。此外，通过一系列功能实验探讨了 AGR2 在乳腺癌进展中的作用。我们发现 DNA 甲基化是调节 AGR2 表达模式的重要机制。AGR2 低表达的患者表现出免疫“热”和免疫抑制表型，其特征是肿瘤免疫细胞浸润丰富，转化生长因子-β（TGF-β）和上皮间质转化途径的富集评分增加，而 AGR2 高表达的患者表现出相反的免疫特征，缺乏免疫细胞浸润，提示免疫“冷”和荒漠表型。此外，单细胞分析进一步表明，恶性细胞中的 AGR2 通过协调细胞因子-趋化因子信号和免疫浸润来改变细胞间相互作用。值得注意的是，两个免疫治疗队列表明，AGR2 共表达基因可以作为患者生存的预后指标。总之，AGR2 通过影响肿瘤免疫微环境促进乳腺癌的进展。AGR2 低表达的患者可能适合与免疫检查点抑制剂和 TGF-β 阻滞剂联合治疗。因此，本研究为制定针对乳腺癌患者的个性化免疫治疗策略提供了理论基础。
