DSpace Collection:https://hdl.handle.net/10171/227262024-03-29T10:42:53Z2024-03-29T10:42:53ZRegulation and role of the PP2A-B56 holoenzyme family in cancerhttps://hdl.handle.net/10171/678322023-11-13T06:05:30Z2023-01-01T00:00:00ZTitle: Regulation and role of the PP2A-B56 holoenzyme family in cancer
Abstract: Protein phosphatase 2A (PP2A) inactivation is common in cancer, leading to sustained activation of pro-survival and growth-promoting pathways. PP2A consists of a scaffolding A-subunit, a catalytic C-subunit, and a regulatory B-subunit. The functional complexity of PP2A holoenzymes arises mainly through the vast repertoire of regulatory B-subunits, which determine both their substrate specificity and their subcellular localization. Therefore, a major challenge for developing more effective therapeutic strategies for cancer is to identify the specific PP2A complexes to be targeted. Of note, the development of small molecules specifically directed at PP2A-B56 & alpha; has opened new therapeutic avenues in both solid and hematological tumors. Here, we focus on the B56/PR61 family of PP2A regulatory subunits, which have a central role in directing PP2A tumor suppressor activity. We provide an overview of the mechanisms controlling the formation and regulation of these complexes, the pathways they control, and the mechanisms underlying their deregulation in cancer.2023-01-01T00:00:00ZICAM-1-LFA-1 dependent CD8+ T-Lymphocyte aggregation in tumor tissue prevents recirculation to draining lymph nodeshttps://hdl.handle.net/10171/566472020-03-17T09:03:41Z2018-09-12T00:00:00ZTitle: ICAM-1-LFA-1 dependent CD8+ T-Lymphocyte aggregation in tumor tissue prevents recirculation to draining lymph nodes
Abstract: The quantity of T-lymphocytes reaching the draining lymph nodes from tumors is likely
important to mount effective distant responses and for the establishment of long term
systemic memory. Looking into mechanisms behind lymphocyte egress, we directed
our attention to leukocyte adhesion mechanisms inside tumors. Here we demonstrate
that activated T-cells form intra-tumor aggregates in a LFA-1-ICAM-1-dependent fashion
in mouse models of melanoma and breast cancer. We also provide evidence of the
presence of T-cell clusters in primary human melanoma. Disruption of LFA-1-ICAM-1
interactions, and thereby T-cell clustering, enhances the arrival of activated CD8+
T-cells to tumor draining lymph nodes in both transplanted and spontaneous cancer
models. Interestingly, upon ICAM-1 blockade, the expression of the chemotactic
receptor CCR7 augments in tumor infiltrating lymphocytes and in in-vitro de-clustered
T cells, as well as their ability to transmigrate across lymphatic endothelial cells. We
propose that ICAM-1-mediated homotypic T-lymphocyte aggregation may serve as a
tumor-mediated immune retention mechanism entrapping activated CD8+ T cells in
the tumor microenvironment. Modulation of T-cell adhesion may be of use to improve
the transit of activated lymphocytes toward the lymph nodes and their subsequent
recirculation.2018-09-12T00:00:00ZAssociation of phagocytic NADPH oxidase activity with hypertensive heart disease: a role for cardiotrophin-1?https://hdl.handle.net/10171/359682020-03-04T06:36:35Z2014-01-01T00:00:00ZTitle: Association of phagocytic NADPH oxidase activity with hypertensive heart disease: a role for cardiotrophin-1?
Abstract: Left ventricular hypertrophy (LVH) is an independent marker of mortality in hypertension. Although the
mechanisms contributing to LVH are complex, inflammation and oxidative stress may favor its development. We analyzed
the association of the phagocytic NADPH oxidase–mediated superoxide anion release and LVH in patients with essential
hypertension and the role of cardiotrophin-1 (CT-1) and interleukin-6 (IL-6), cytokines implicated in cardiac growth.
Blood pressure, echocardiography data, and serum CT-1 and IL-6 levels were obtained in 140 subjects: 18 normotensives
without LVH, 42 hypertensives without LVH, and 80 hypertensives with LVH. The NADPH oxidase–dependent superoxide
production was assessed by chemiluminescence in peripheral blood mononuclear cells. Peripheral blood mononuclear
cells were stimulated with CT-1 in vitro. Superoxide anion production by peripheral blood mononuclear cells associated
with LVH and correlated with the left ventricular mass index. Serum CT-1 and IL-6 levels, which associated with the
left ventricular mass index, correlated with superoxide production. Serum CT-1 and IL-6 levels were correlated. CT-1
stimulated NADPH oxidase superoxide production in peripheral blood mononuclear cells, which resulted in an increased
release of IL-6. Our results show that superoxide anion production by the phagocytic NADPH oxidase associates with
hypertensive heart disease, being significantly enhanced in hypertensive patients with LVH. This may be attributable to
the activation of the NADPH oxidase by CT-1 and the subsequent release of IL-6. The phagocytic NADPH oxidase may be a therapeutic target in hypertensive heart disease2014-01-01T00:00:00ZDendritic cells take up and present antigens from viable and apoptotic polymorphonuclear leukocyteshttps://hdl.handle.net/10171/203692020-03-17T09:03:41Z2011-01-01T00:00:00ZTitle: Dendritic cells take up and present antigens from viable and apoptotic polymorphonuclear leukocytes
Abstract: Dendritic cells (DC) are endowed with the ability to cross-present antigens from other cell types to cognate T cells. DC are poised to meet polymorphonuclear leukocytes (PMNs) as a result of being co-attracted by interleukin-8 (IL-8), for instance as produced by tumor cells or infected tissue. Human monocyte-derived and mouse bone marrow-derived DC can readily internalize viable or UV-irradiated PMNs. Such internalization was abrogated at 4°C and partly inhibited by anti-CD18 mAb. In mice, DC which had internalized PMNs containing electroporated ovalbumin (OVA) protein, were able to cross-present the antigen to CD8 (OT-1) and CD4 (OT-2) TCR-transgenic T cells. Moreover, in humans, tumor cell debris is internalized by PMNs and the tumor-cell material can be subsequently taken up from the immunomagnetically re-isolated PMNs by DC. Importantly, if human neutrophils had endocytosed bacteria, they were able to trigger the maturation program of the DC. Moreover, when mouse PMNs with E. coli in their interior are co-injected in the foot pad with DC, many DC loaded with fluorescent material from the PMNs reach draining lymph nodes. Using CT26 (H-2(d)) mouse tumor cells, it was observed that if tumor cells are intracellularly loaded with OVA protein and UV-irradiated, they become phagocytic prey of H-2(d) PMNs. If such PMNs, that cannot present antigens to OT-1 T cells, are immunomagnetically re-isolated and phagocytosed by H-2(b) DC, such DC productively cross-present OVA antigen determinants to OT-1 T cells. Cross-presentation to adoptively transferred OT-1 lymphocytes at draining lymph nodes also take place when OVA-loaded PMNs (H-2(d)) are coinjected in the footpad of mice with autologous DC (H-2(b)). In summary, our results indicate that antigens phagocytosed by short-lived PMNs can be in turn internalized and productively cross-presented by DC.2011-01-01T00:00:00Z