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

Abstract

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.

• Authors: Xi Chen, Qianqian Shao, Shengnan Hao, Zhonghua Zhao, Yang Wang, Xiaofan Guo, Ying He, Wenjuan Gao, Haiting Mao
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 8 Pg. 13703-13715 (Feb 21 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28099147 (Publication Type: Journal Article)

Chemical References

• CTLA-4 Antigen
• CTLA4 protein, human
• Cytokines

Topics

• Antigen Presentation
• Breast Neoplasms (immunology, metabolism, pathology)
• CD4-Positive T-Lymphocytes (immunology, pathology)
• CTLA-4 Antigen (antagonists & inhibitors, biosynthesis, immunology)
• Cytokines (biosynthesis, immunology)
• Dendritic Cells (immunology, pathology)
• Female
• Flow Cytometry
• Humans
• MCF-7 Cells
• Monocytes (immunology, pathology)
• Th1 Cells (immunology, pathology)