Cancer stem cell-derived CHI3L1 activates the MAF/CTLA4 signaling pathway to promote immune escape in triple-negative breast cancer
- J Transl Med. 2023 Oct 14;21(1):721. doi: 10.1186/s12967-023-04532-6.
- 1. Special Medical Service Center, General Surgery, Zhujiang Hospital of Southern Medical University, No. 253, Middle Gongye Avenue, Haizhu District, Guangzhou, 510280, Guangdong, People's Republic of China.
- 2. Department of Breast Surgery, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China.
- 3. Department of Breast Surgery, Maternity and Children's Healthcare Hospital of Foshan, Foshan, 528000, People's Republic of China.
- 4. Special Medical Service Center, General Surgery, Zhujiang Hospital of Southern Medical University, No. 253, Middle Gongye Avenue, Haizhu District, Guangzhou, 510280, Guangdong, People's Republic of China. [email protected].
- # Contributed equally.
Background: Triple-Negative Breast Cancer (TNBC) development may be associated with tumor immune escape. This study explores whether the CHI3L1/MAF/CTLA4/S100A4 axis affects immune escape in TNBC through interplay with Triple-Negative Breast Cancer stem cells (TN-BCSCs).
Objective: The aim of this study is to utilize single-cell transcriptome Sequencing (scRNA-seq) to uncover the molecular mechanisms by which the CHI3L1/MAF/CTLA4 signaling pathway may mediate immune evasion in Triple-Negative Breast Cancer through the interaction between tumor stem cells (CSCs) and immune cells.
Methods: Cell subsets in TNBC tissues were obtained through scRNA-seq, followed by screening differentially expressed genes in TN-BCSCs and B.C.s (CD44+ and CD24-) and predicting the transcription factor regulated by CHI3L1. Effect of CHI3L1 on the stemness phenotype of TNBC cells investigated. Effects of BCSCs-231-derived CHI3L1 on CTLA4 expression in T cells were explored after co-culture of BCSCs-231 cells obtained from microsphere culture of TN-BCSCs with T cells. BCSCs-231-treated T cells were co-cultured with CD8+ T cells to explore the resultant effect on T cell cytotoxicity. An orthotopic B.C. transplanted tumor model in mice with humanized immune systems was constructed, in which the Role of CHI3L1/MAF/CTLA4 in the immune escape of TNBC was explored.
Results: Eight cell subsets were found in the TNBC tissues, and the existence of TN-BCSCs was observed in the epithelial cell subset. CHI3L1 was related to the stemness phenotype of TNBC cells. TN-BCSC-derived CHI3L1 increased CTLA4 expression in T cells through MAF, inhibiting CD8+ T cell cytotoxicity and inducing Immunosuppression. Furthermore, the CTLA4+ T cells might secrete S100A4 to promote the stemness phenotype of TNBC cells.
Conclusions: TN-BCSC-derived CHI3L1 upregulates CTLA4 expression in T cells through MAF, suppressing the function of CD8+ T cells, which promotes the immune escape of TNBC.
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