Anterior gradient-2 regulates cell communication by coordinating cytokine-chemokine signaling and immune infiltration in breast cancer.

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.