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.
Highlights
Breast cancer is the predominant type of cancer among women in both developed and developing countries, representing the leading cause of cancer-related female mortality worldwide
At day 5, human monocyte-derived Immature DCs (imDCs) were cocultured with Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)+breast cancer cells (BCCs) in vitro in the presence of LPS for another 2 days, while soluble CTLA-4-Fctreated dendritic cells (DCs) were acted as the positive control
CTLA-4, constitutively expressed at a high level on regulatory T cells (Tregs), is a negative regulator of T-cell activation which binding to CD80/CD86 molecules expressed on DCs interrupts CD28 mediated signaling to T cells [24]
Summary
Breast cancer is the predominant type of cancer among women in both developed and developing countries, representing the leading cause of cancer-related female mortality worldwide. Studies have shown that patients of breast cancer have lower absolute numbers of peripheral blood lymphocytes but increased numbers of functionally suppressive CD4+CD25+ regulatory T cells (Tregs) in the peripheral blood and tumor microenvironment [2, 3]. It is well known that DCs appear susceptible to tumormediated immunosuppression [5] Both circulating and tumor-infiltrating DCs are functionally impaired in tumor-bearing animals and in cancer patients. Inhibition of DCs maturation and function is the common mode to evade immune surveillance by tumor cells [6]. It has been reported that ex vivo Tregs down-modulate B7-molecules (CD80 and CD86) on cocultured DCs in a cell-contact dependent way and the extent of downmodulation is functionally significant because Tregsconditioned DCs induce poor T-cell proliferation response [7]. The down-modulation is inhibited by www.impactjournals.com/oncotarget blocking cytotoxic T lymphocyte antigen-4 (CTLA-4, known as CD152) [7]
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