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

X Chen, Q Shao, S Hao, Z Zhao, Y Wang, X Guo… - Oncotarget, 2017 - ncbi.nlm.nih.gov
X Chen, Q Shao, S Hao, Z Zhao, Y Wang, X Guo, Y He, W Gao, H Mao
Oncotarget, 2017ncbi.nlm.nih.gov
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 …
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.
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