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

// Xi Chen 1 , Qianqian Shao 1 , Shengnan Hao 1 , Zhonghua Zhao 1 , Yang Wang 1 , Xiaofan Guo 2 , Ying He 1 , Wenjuan Gao 1 , Haiting Mao 1 1 Institute of Basic Medicial Sciences, Qi Lu Hospital, Shandong University, Jinan, Shandong Province, 250012, P.R.China 2 Department of Neurosurgery, Qi Lu Hospital, Shandong University, Jinan, Shandong Province, 250012, P.R.China Correspondence to: Haiting Mao, email: haitingmao@yahoo.com Keywords: breast cancer cell, CTLA-4, dendritic cell, CD4 + T cell, CD8 + T cell Received: November 14, 2016      Accepted: January 04, 2017      Published: January 13, 2017 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.