title: Recombinant Parvoviruses Armed to Deliver CXCL4L1 and CXCL10 Are Impaired in Their Antiangiogenic and Antitumoral Effects in a Kaposi Sarcoma Tumor Model Due To the Chemokines' Interference with the Virus Cycle.
abstract: Application of oncolytic viruses is a valuable option to broaden the armament of anticancer therapies, as these combine specific cytotoxic effects and immune-stimulating properties. The self-replicating H-1 parvovirus (H-1PV) is a prototypical oncolytic virus that, besides targeting tumor cells, also infects endothelial cells, thus combining oncolytic and angiostatic traits. To increase its therapeutic value, H-1PV can be armed with cytokines or chemokines to enhance the immunological response. Some chemokines-more specifically, the CXCR3 ligands CXCL4L1 and CXCL10-combine immune-stimulating properties with angiostatic activity. This study explores the therapeutic value of recombinant parvoviruses carrying CXCL4L1 or CXCL10 transgenes (Chi-H1/CXCL4L1 or Chi-H1/CXCL10, respectively) to inhibit the growth of the human Kaposi sarcoma cell line KS-IMM. KS-IMM cells infected by Chi-H1/CXCL4L1 or Chi-H1/CXCL10 released the corresponding chemokine and showed reduced migratory capacity. Therefore, the antitumoral capacity of Chi-H1/CXCL4L1 or Chi-H1/CXCL10 was tested in mice. Either in vitro infected KS-IMM cells were injected or subcutaneously growing KS-IMM xenografts were treated by peritumoral injections of the different viruses. Surprisingly, the transgenes did not increase the antitumoral effect of natural H-1PV. Further experiments indicated that CXCL4L1 and CXCL10 interfered with the expression of the viral NS1 protein in KS-IMM cells. These results indicate that the outcome of parvovirus-based delivery of CXCR3 ligands might be tumor cell type dependent, and hence its application must be considered carefully.
authors.affiliation: 1 Division of Tumor Virology, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Dinsart
authors.affiliation: 1 Division of Tumor Virology, German Cancer Research Center , Heidelberg, Germany.|2 Laboratory of Molecular Immunology, Department of Microbiology and Immunology, KU Leuven, Rega Institute for Medical Research , Leuven, Belgium .
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Pervolaraki
authors.affiliation: 1 Division of Tumor Virology, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stroh-Dege
authors.affiliation: 1 Division of Tumor Virology, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Muriel
authors.initials: M
authors.lastname: Lavie
authors.affiliation: 2 Laboratory of Molecular Immunology, Department of Microbiology and Immunology, KU Leuven, Rega Institute for Medical Research , Leuven, Belgium .
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ronsse
authors.affiliation: 1 Division of Tumor Virology, German Cancer Research Center , Heidelberg, Germany.
authors.forename: Jean
authors.initials: J
authors.lastname: Rommelaere
authors.affiliation: 2 Laboratory of Molecular Immunology, Department of Microbiology and Immunology, KU Leuven, Rega Institute for Medical Research , Leuven, Belgium .
authors.forename: Jo
authors.initials: J
authors.lastname: Van Damme
authors.affiliation: 2 Laboratory of Molecular Immunology, Department of Microbiology and Immunology, KU Leuven, Rega Institute for Medical Research , Leuven, Belgium .
authors.forename: Katrien
authors.initials: K
authors.lastname: Van Raemdonck
authors.affiliation: 2 Laboratory of Molecular Immunology, Department of Microbiology and Immunology, KU Leuven, Rega Institute for Medical Research , Leuven, Belgium .
authors.forename: Sofie
authors.initials: S
authors.lastname: Struyf
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D054357:Chemokine CXCL10 / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D017992:Parvovirus / Q000235:genetics*; D010978:Platelet Factor 4 / Q000235:genetics*; D012514:Sarcoma, Kaposi / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D054357:Chemokine CXCL10; C064936:PF4V1 protein, human; D010978:Platelet Factor 4
keywords: CXCL10; CXCL4L1; CXCR3; angiostatic chemokines; cancer therapy; parvovirus