title: LFA-1-targeting Leukotoxin (LtxA; Leukothera®) causes lymphoma tumor regression in a humanized mouse model and requires caspase-8 and Fas to kill malignant lymphocytes.
abstract: Leukotoxin (LtxA) is a protein secreted from the oral bacterium Aggregatibacter actinomycetemcomitans. LtxA binds to the β2 integrin lymphocyte-associated function antigen-1 (LFA-1) on human white blood cells (WBCs), resulting in cell death. LtxA is currently under investigation as a novel therapy (Leukothera(®)) for treating hematologic malignancies and autoimmune diseases. We show here that LtxA has potent in vivo anti-lymphoma activity in mice. LtxA caused complete regression of B-cell tumors and promoted long-term survival of mice. The mechanism of LtxA-mediated killing of malignant lymphocytes was further examined. We found that LtxA kills malignant lymphocytes by a novel mechanism requiring the death receptor Fas and caspase-8, but not Fas ligand (FasL) or caspase-9. We also determined that LFA-1 and Fas are closely associated on the cell surface and this proximity of LFA-1 and Fas could explain how signaling through an integrin can lead to cell death. In addition to LFA-1, this work reveals a second surface protein, Fas, that is critical for LtxA-mediated cell death. Knowledge of the mechanism of cell death induced by LtxA will facilitate the development and understanding of this potent experimental therapeutic agent.
authors: From the Department of Oral Biology, Rutgers School of Dental Medicine, Newark, NJ 07103, United States.
authors: Kristina M
authors: KM
authors: DiFranco
authors: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, United States.
authors: Nadine
authors: N
authors: Johnson-Farley
authors: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, United States.
authors: Joseph R
authors: JR
authors: Bertino
authors: From the Department of Oral Biology, Rutgers School of Dental Medicine, Newark, NJ 07103, United States.
authors: David
authors: D
authors: Elson
authors: From the Department of Oral Biology, Rutgers School of Dental Medicine, Newark, NJ 07103, United States.
authors: Brian A
authors: BA
authors: Vega
authors: Actinobac Biomed, Inc., North Brunswick, NJ 08902, United States.
authors: Benjamin A
authors: BA
authors: Belinka
authors: From the Department of Oral Biology, Rutgers School of Dental Medicine, Newark, NJ 07103, United States; Actinobac Biomed, Inc., North Brunswick, NJ 08902, United States. Electronic address: kachlasc@rutgers.edu.
authors: Scott C
authors: SC
authors: Kachlany
mesh_terms: D016976:Aggregatibacter actinomycetemcomitans / Q000737:chemistry; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001427:Bacterial Toxins / Q000737:chemistry / Q000494:pharmacology*; D053181:Caspase 8 / Q000378:metabolism*; D053453:Caspase 9 / Q000378:metabolism; D016503:Drug Delivery Systems; D005098:Exotoxins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D019169:Jurkat Cells; D016169:Lymphocyte Function-Associated Antigen-1; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D001427:Bacterial Toxins; D005098:Exotoxins; C491901:FAS protein, human; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D019014:fas Receptor; C018579:leukotoxin; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9
keywords: Autoimmune disease; Cell death; Inflammation; Integrin; Lymphocytes; Lymphoma