Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis.
ABSTRACT Chemotherapy has been widely used in cancer treatment. However, the prognosis of the cancer patients following chemotherapy has not been substantially improved. Alternative strategies such as immunotherapy and their combinations with chemotherapy are now being considered. Yet, the effects of chemotherapy on the immune responses of cancer cells are not clear. Cancer immunoresistance and immune escape are major obstacles in immunotherapy. In the present studies, we examined the effects of chemopreventive agents, paclitaxel, etoposide and 5-fluorouracil, on the surface expression of programmed death-1-ligand 1 (PD-L1), a negative regulator of T cell anti-tumor immunity. Interaction of PD-L1 on cancer cells with programmed death receptor 1 (PD-1) on T cells has been reported to inhibit the proliferation of tumor-reactive cytotoxic T cells and induce T cell apoptosis, which could be an important mechanism in the development of cancer immunoresistance. We demonstrated that those chemopreventive agents were able to induce PD-L1 surface expression in human breast cancer cells, which then promoted PD-L1-mediated T cell apoptosis. Our studies reveal a potential link between chemotherapy and cancer immunoresistance.
Article: Doxorubicin downregulates cell surface B7-H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an anti-apoptotic molecule.[show abstract] [hide abstract]
ABSTRACT: B7-H1 (PD-L1, CD274) is a T cell inhibitory molecule expressed in many types of cancer, leading to immune escape of tumor cells. Indeed, in previous reports we have shown an association of B7-H1 expression with high-risk breast cancer patients. In the current study, we used immunohistochemistry, immunofluorescence and Western blot techniques to investigate the effect of neoadjuvant chemotherapy on the expression of B7-H1 in breast cancer cells. Among tested chemotherapeutic agents, doxorubicin was the most effective in downregulating cell surface expression of B7-H1 in vitro. These results were validated in vivo in a xenograft mouse model, as well as in murine heart tissue known to constitutively express B7-H1. The doxorubicin-dependent cell surface downregulation of B7-H1 was accompanied by an upregulation of B7-H1 in the nucleus. This re-distribution of B7-H1 was concurrent with a similar translocation of phosphorylated AKT to the nucleus. Inhibition of the PI3K/AKT pathway abrogated the doxorubicin-mediated nuclear up-regulation of B7-H1, suggesting an involvement of PI3K/AKT pathway in the nuclear up-regulation of B7-H1. Interestingly, siRNA knock down of B7-H1 lead to an increase in spontaneous apoptosis, as well as doxorubicin-induced apoptosis, which indicates an anti-apoptotic role for B7-H1 in breast cancer cells. The novel discovery of B7-H1 expression in the nuclei of breast cancer cells suggests that B7-H1 has functions other than inhibition of T cells. Our findings explain the previously reported immunomodulatory effect of anthracyclines on cancer cells, and provide a link between immunoresistance and chemoresistance. Finally these results suggest the use of dual combinatorial agents to inhibit B7-H1 beside chemotherapy, in breast cancer patients.Breast cancer research: BCR 01/2010; 12(4):R48. · 5.24 Impact Factor
Article: The chemotherapeutic drug oxaliplatin differentially affects blood DC function dependent on environmental cues.[show abstract] [hide abstract]
ABSTRACT: It has become evident that the tumor microenvironment plays a pivotal role in the maintenance of cancerous growth. One of the acquired functions of the tumor microenvironment is the suppression of immune responses. Indeed, blocking the inhibitory pathways operational in the microenvironment results in enhanced T-cell-dependent, anti-tumor immunity. Chemotherapeutic drugs not only directly kill tumor cells but also shape the tumor microenvironment and potentiate anti-tumor immunity. Here, we demonstrate that the chemotherapeutic compound oxaliplatin acts as a double-edged sword. Besides killing tumor cells, oxaliplatin bolsters immunosuppressive pathways, resulting in decreased activation of T cells by human plasmacytoid dendritic cells (pDCs). Exposure to oxaliplatin markedly increased expression of the T-cell inhibitory molecule programmed death receptor-ligand 1 (PD-L1) on human pDCs and also TLR9-induced IFNα secretion. Furthermore, oxaliplatin decreased TLR-induced STAT1 and STAT3 expression, and NF-κB-mediated responses. The oxaliplatin induced upregulation of PD-L1 and downregulation of costimulatory molecules CD80 and CD86 resulted in decreased T-cell proliferation. Our results demonstrate that platinum-based anticancer drugs adapt TLR-induced signaling in human pDCs and myeloid DCs (mDCs), thereby downgrading their immunostimulatory potential.Cancer Immunology and Immunotherapy 12/2011; 61(7):1101-11. · 3.70 Impact Factor
Article: Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling.[show abstract] [hide abstract]
ABSTRACT: Generation and maintenance of immunological tolerance is a pivotal aim in the field of autoimmunity. Regulatory molecules of Programmed Death Ligand-1 (PD-L1), galectin-1 and TGF-β are described as key mediators of peripheral tolerance that actively suppress auto-reactive cells and inhibit their mediated tissue damages. Accordingly, biological intervention in host immune system for induction of peripheral tolerance is pivot to many of the recent studies. Mesenchymal stem cell-derived microvesicles (MVs) are viewed as potential mediators to shed peripheral tolerance toward auto-reactive cells via bearing of tolerogenic molecules. Here, MVs were isolated from mesenchymal stem cell (MSC) cultures' conditioned medium. They were explored for the expression of PD-L1, galectin-1 and membrane bound TGF-β through flow cytometry. The immunoregulatory effects of MVs on splenic mononuclear cells (MNCs) derived from experimental autoimmune encephalomyelitis (EAE) affected mice were investigated using MTT assay, ELISA and flow cytometry. MVs derived from MSCs expressed PD-L1, galecin-1 and membrane-bound TGF-β. MVs exhibited the potential to inhibit auto-reactive lymphocyte proliferation and also the potency to promote them to secret anti-inflammatory cytokines of IL-10 and TGF-β. Interestingly, inducing inflammatory setting on MSCs, revealed the enhancing regulatory effects of MVs via increased expression of some regulatory molecules, specifically PD-L1 and TGF-β. Induction of tolerogenic signaling, promotion of CD4+ CD25+ Foxp3+ regulatory T cells generation and apoptotic activity towards activated T cells are shown to be possible mechanisms involved in MV-mediated regulation. Recent study suggests MSC-derived MVs as potent organelles for induction of peripheral tolerance and modulation of immune responses.Immunology letters 06/2012; 147(1-2):47-54. · 2.91 Impact Factor