CTLA-4 positive breast cancer cells suppress dendritic cells maturation and function

• Published in: Oncotarget 2017-02, Vol.8 (8), p.13703-13715
• Main Authors: Chen, Xi, Shao, Qianqian, Hao, Shengnan, Zhao, Zhonghua, Wang, Yang, Guo, Xiaofan, He, Ying, Gao, Wenjuan, Mao, Haiting
• Format: Article
• Language: English
• Subjects: Antigen Presentation; Breast Neoplasms - immunology; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - pathology; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - biosynthesis; CTLA-4 Antigen - immunology; Cytokines - biosynthesis; Cytokines - immunology; Dendritic Cells - immunology; Dendritic Cells - pathology; Female; Flow Cytometry; Humans; MCF-7 Cells; Monocytes - immunology; Monocytes - pathology; Research Paper; Th1 Cells - immunology; Th1 Cells - pathology
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.14626

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a potent immunoregulatory molecule, can down-regulate T-cell activation and inhibit anti-tumor immune response. This study showed that LPS-stimulated human dendritic cells (DCs) decreased the expression of HLA-DR, CD83 and costimulatory molecules (CD40, CD80 and CD86) following coculturing with CTLA-4+ breast cancer cells. Moreover, the suppressed DCs further inhibited proliferation of allogeneic CD4+/CD8+ T-cells, differentiation of Th1 and function of cytotoxic lymphocytes (CTLs). However, CTLA-4 blockade in breast cancer cells could recover DC maturation and cytokine production, elevate antigen-presenting function of DCs, reverse Th1/CTLs response and cytokine secretion. Subsequent study demonstrated that the activation of extracellular-signal regulated kinase and signal transducer and activator of transcription 3 of DCs caused by CTLA-4+ breast cancer cells were the predominant mechanism of DC suppression. In addition, CTLA-4 blockade treatment also directly inhibited proliferation and induced apoptosis of CTLA-4+ breast cancer cells. Collectively, CTLA-4 was expressed and functional on human breast cancer cells through influencing maturation and function of DCs in vitro, and CTLA-4 blockage not only recovered the antigen-presenting function of DCs and T-cells activation but also suppressed the biological activity of breast cancer cells themselves. This study highlights the clinical application of CTLA-4 blockade therapy in breast cancer.