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

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.