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1. Amplified inhibition of stellate cell activation pathways by PPAR-γ, RAR and RXR agonists.

Author

Efrat Sharvit, Shirley Abramovitch, Shimon Reif, and Rafael Bruck

Subjects
Medicine, Science
Abstract

Peroxisome proliferator activator receptors (PPAR) ligands such as 15-Δ12,13-prostaglandin L(2) [PJ] and all trans retinoic acid (ATRA) have been shown to inhibit the development of liver fibrosis. The role of ligands of retinoic X receptor (RXR) and its ligand, 9-cis, is less clear. The purpose of this study was to investigate the effects of combined treatment of the three ligends, PJ, ATRA and 9-cis, on key events during liver fibrosis in rat primary hepatic stellate cells (HSCs). We found that the anti-proliferative effect of the combined treatment of PJ, ATRA and 9-cis on HSCs was additive. Further experiments revealed that this inhibition was due to cell cycle arrest at the G0/G1 phase as demonstrated by FACS analysis. In addition, the combined treatment reduced cyclin D1 expression and increased p21 and p27 protein levels. Furthermore, we found that the three ligands down regulated the phosphorylation of mTOR and p70(S6K). The activation of HSCs was also inhibited by the three ligands as shown by inhibition of vitamin A lipid droplets depletion from HSCs. Studies using real time PCR and western blot analysis showed marked inhibition of collagen Iα1 and αSMA by the combination of the three ligands. These findings suggest that the combined use of PJ, ATRA and 9-cis causes inhibition of cell proliferation by cell cycle arrest and down-regulation of fibrotic markers to a greater extent compared to each of the ligands alone.

Published
2013
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2. Biomimetic Glyconanoparticle Vaccine for Cancer Immunotherapy

Author

Xi Chen, Roberto Duchi, Vered Padler-Karavani, Shirley Abramovitch, Eliran Moshe Reuven, Shani Leviatan Ben-Arye, Jean-Paul Soulillou, Andrea Perota, Cesare Galli, Sophie Conchon, Hai Yu, Department of Cell Research and Immunology, Tel Aviv University [Tel Aviv], Department of Chemistry [Davis, CA, USA], University of California [Davis] (UC Davis), University of California-University of California, Avantea Laboratory of Reproductive Technologies [Cremona, Italy], Immunoregulation And Immunointervention in Transplantation and Autoimmunity (Team 4 - U1064 Inserm - CRTI), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Fondazione Avantea [Cremona, Italy], European Project: ERC-2016-STG-716220, Tel Aviv University (TAU), Department of Chemistry [Univ California Davis] (Chemistry - UC Davis), University of California (UC)-University of California (UC), Le Bihan, Sylvie, and European Union H2020 Program - ERC-2016-STG-716220 - INCOMING

Subjects
Swine, medicine.medical_treatment, General Physics and Astronomy, 02 engineering and technology, 01 natural sciences, Mice, Cancer immunotherapy, Biomimetic Materials, General Materials Science, Cancer, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, General Engineering, biomimetic, 021001 nanoscience & nanotechnology, 3. Good health, 5.1 Pharmaceuticals, glycan microarray, sialic acid, Colonic Neoplasms, Immunotherapy, Development of treatments and therapeutic interventions, Antibody, 0210 nano-technology, Biotechnology, N-glycolylneuraminic acid, Knockout, Context (language use), Adenocarcinoma, 010402 general chemistry, Cancer Vaccines, Article, Vaccine Related, Immune system, Antigen, medicine, Animals, Particle Size, Nanoscience & Nanotechnology, glyconanoparticle, Nutrition, cancer immunotherapy, Prevention, N-Acetylneuraminic Acid, neoantigen, 0104 chemical sciences, Good Health and Well Being, Immunization, Cancer research, biology.protein, Nanoparticles, Neuraminic Acids, Cancer vaccine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Cancer immunotherapy aims to harness the immune system to combat malignant processes. Transformed cells harbor diverse modifications that lead to formation of neoantigens, including aberrantly expressed cell surface carbohydrates. Targeting tumor-associated carbohydrate antigens (TACA) hold great potential for cancer immunotherapy. N-glycolylneuraminic acid (Neu5Gc) is a dietary non-human immunogenic carbohydrate that accumulates on human cancer cells, thereby generating neoantigens. In mice, passive immunotherapy with anti-Neu5Gc antibodies inhibits growth of Neu5Gc-positive tumors. Here, we designed an active cancer vaccine immunotherapy strategy to target Neu5Gc-positive tumors. We generated biomimetic glyconanoparticles using engineered αGal knockout porcine red blood cells to form nanoghosts (NGs) that either express (NG[pos]) or lack expression (NG[neg]) of Neu5Gc-glycoconjugates in their natural context. We demonstrated that optimized immunization of "human-like" Neu5Gc-deficient Cmah[−/−] mice with NG[pos] glyconanoparticles induce a strong, diverse and persistent anti-Neu5Gc IgG immune response. The resulting anti-Neu5Gc IgG antibodies were also detected within Neu5Gc-positive tumors and inhibited tumor growth in vivo. Using detailed glycan microarray analysis, we further demonstrate that the kinetics and quality of the immune responses influence the efficacy of the vaccine. These findings reinforce the potential of TACA neoantigens and the dietary non-human sialic acid Neu5Gc, in particular, as immunotherapy targets.

Published
2019

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