Highly efficient, in-vivo Fas-mediated apoptosis of B-cell lymphoma by hexameric CTLA4-FasL

• Published in: Journal of hematology and oncology 2014-09, Vol.7 (1), p.64-64, Article 64
• Main Authors: Aronin, Alexandra, Amsili, Shira, Prigozhina, Tatyana B, Tzdaka, Kobi, Shen, Roy, Grinmann, Leonid, Szafer, Fanny, Edebrink, Per, Rauvola, Mari-Anne, Shani, Noam, Elhalel, Michal Dranitzki
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Blotting, Western; Cell Line, Tumor; Chromatography, High Pressure Liquid; Cross-Linking Reagents - chemical synthesis; Cross-Linking Reagents - therapeutic use; CTLA-4 Antigen - therapeutic use; Enzyme-Linked Immunosorbent Assay; Fas Ligand Protein - therapeutic use; fas Receptor - metabolism; Female; Flow Cytometry; Hematology; Humans; Isoelectric Focusing; Lymphocytes; Lymphoma; Lymphoma, B-Cell - pathology; Medical prognosis; Mice; Mice, Nude; Molecular structure; Molecular weight; Oncology; Proteins; Recombinant Fusion Proteins - chemical synthesis; Recombinant Fusion Proteins - therapeutic use; Studies; Xenograft Model Antitumor Assays
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-014-0064-6

Non-Hodgkin lymphomas (NHLs) account for 4% of all malignancies. 5-year survival rate increased to 50% with new treatment modalities, however there is need for new effective treatment for the more aggressive, relapsing forms. Recently, CTLA4-FasL, that can bind to B7 and Fas receptor (Fas), was shown to induce robust apoptosis of cell lines originating from B cell lymphomas expressing both B7 and Fas, by activating pro-apoptotic signals in parallel to abrogating anti-apoptotic ones. The present study focuses on the unique properties of CTLA4-FasL as a potent apoptosis inducer of malignant cells in-vitro and in a xenograft model. CTLA4-FasL was found to naturally form a stable homo-hexamer. CTLA4-FasL induces robust apoptosis of a large variety of malignant cells while relatively sparing non-malignant ones, being more efficient when both receptors (B7 and Fas) are expressed on target cells. Even in non-B7 expressing cells, CTLA4-FasL exhibited better apoptotic activity than its parts, alone or in combination, however, only in B7 expressing cells apoptosis occurs at low concentrations and CTLA4-FasL induces activation of apoptotic signals and reduces anti-apoptotic ones. Importantly, CTLA4-FasL efficiently inhibited the growth of human B cell lineage tumors in a xenograft model, by provoking tumor cells' apoptosis. Thus, CTLA4-FasL, a natural homo-hexamer protein, induces robust apoptosis of malignant cells, in-vitro and in-vivo. In B-cell lymphoma, its potency stems from the combination of its synergistic effect of activating the caspases while abrogating the anti-apoptotic signaling, with its unique hexameric structure, making CTLA4-FasL a promising candidate for aggressive B cell lymphomas treatment.