RESUMEN
BACKGROUND: Viscum album L. (VA) preparations possess immunomodulatory properties and are used in complementary medicine to support cancer therapy. It is unclear if there is an impact of VA on the expression of immune checkpoint proteins on the surface of cancer cells. This study was designed to investigate the role of commercially available VA preparations on checkpoint programmed death ligand 1, 2 (PD-L1, PD-L2) and on major histocompatibility complex class I (MHC-I). METHODS: Four human cancer cell lines (prostate, colon, lung, and breast) were assayed for their PD-L1, PD-L2, and MHC-I level after stimulation with interferon-gamma (IFN-γ). The toxicity of mistletoe preparations for the cells was analysed. Afterwards, the effect of mistletoe preparations on the PD ligands and MHC-I was investigated. RESULTS: Surface protein analysis demonstrated that all tested tumour cell lines increased the PD-L1, PD-L2, and MHC-I-expression, but to different extents, after IFN-γ stimulation. Treatment with VA extracts did not influence the viability of the cells. The expression of PD ligands and MHC-I was not affected by incubation with the VA preparations. CONCLUSION: Our investigation concludes that VA treatment does not interfere with the expression of PD ligands or MHC-I among selected cancer cells.
Asunto(s)
Neoplasias de la Mama , Viscum album , Masculino , Humanos , Antígeno B7-H1 , Neoplasias de la Mama/tratamiento farmacológico , Interferón gamma , Próstata , Pulmón , ColonRESUMEN
Inclusion body myositis (IBM) is an inflammatory myopathy of aged people with poor response to therapy. To characterize muscle-invading inflammatory cells, we performed immunohistochemical and ultrastructural studies on muscle biopsies from 10 patients with IBM with durations of illness from 3 to 84 months. At the surface of muscle fibers, 79% and 48% of CD8+ cells were positive for killer cell lectin-like receptor subfamily G, member 1 (KLRG1) and CD57, respectively. CD8+KLRG1+ cells are highly differentiated cytotoxic cells. On an average, 27% of CD8-CD57+KLRG1+ cells at the surface were CD4+. Proportions of CD28+ cells among KLRG1+ cells showed a negative correlation with duration of illness (r = -0.68). These changes indicated progressive differentiation of CD8+ T cells. Moreover, PD-1 expression on CD57+ and CD8+ cells increased early, then fluctuated, and reincreased in later stages. PD ligand-1 (PD-L1) and PD-L2 were expressed on adjacent cells including muscle fibers. T cell large granular lymphocytes (LGLs) are potent effector cells and cells with ultrastructure indistinguishable from LGLs were seen in the sarcoplasm along with lymphocytes undergoing degeneration. Together, along the course of IBM, some inflammatory cells retained the potential for cytotoxicity whereas others indicated suppression by exhaustion, senescence, or through the PD-1 pathway.
Asunto(s)
Miositis por Cuerpos de Inclusión , Antígeno B7-H1/metabolismo , Antígenos CD28/metabolismo , Linfocitos T CD8-positivos/metabolismo , Humanos , Ligandos , Fibras Musculares Esqueléticas/patología , Miositis por Cuerpos de Inclusión/patología , Fenotipo , Receptor de Muerte Celular Programada 1/metabolismo , Receptores Similares a Lectina de Células NK/metabolismoRESUMEN
Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Antígeno B7-H1/inmunología , Humanos , Ipilimumab , Melanoma/inmunología , Metástasis de la Neoplasia , Nivolumab , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/inmunologíaRESUMEN
BACKGROUND: Programmed death-1 (PD-1) costimulation acts as a negative regulator of T-cell responses to allografts. However, the role of the PD-1 pathway in xenotransplantation is not well defined yet. We have shown previously that human in vitro T-cell responses to porcine transfectants overexpressing PD-Ligand1 (L23-PD-L1 cells) are remarkably weak. In this report, we asked whether the PD-1/PD-L1 pathway has the potential to diminish xenogeneic immune responses also in vivo. METHODS: L23-PD-L1 or mock transfected control cells (L23-GFP) were transplanted under the kidney capsule of rats. The occurrence of kidney-infiltrating rat leukocytes and the induction of anti-pig antibodies were monitored in grafted animals. RESULTS: Assessment of cellular infiltrates revealed similar numbers of macrophages in kidneys grafted with L23-PD-L1 or L23-GFP control cells. However, the level of MHC class-II molecules was reduced on macrophages responding to L23-PD-L1 grafts, suggesting a lower state of activation. Furthermore, less T cells were found in kidneys receiving L23-PD-L1 cells. In addition, the titers of induced anti-pig antibodies were significantly lower in rats grafted with L23-PD-L1 cells. CONCLUSIONS: These data suggest that signals triggered by PD-1-PD-L1 interaction interfere with activation pathways involved in the induction of cellular and antibody-mediated immune responses to xenografts in vivo. Targeting of PD-1 and/or PD-L1 may be a promising approach for immune modulation after xenotransplantation.