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 anti-cancer 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. In this study, we explore 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, we tested the anti-tumoral capacity of Chi-H1/CXCL4L1 or Chi-H1/CXCL10 in mice. Either in vitro infected KS IMM cells were injected or subcutaneously growing KS IMM xenografts were treated by peri-tumoral injections of the different viruses. Surprisingly, the transgenes did not increase the anti-tumoral effect of natural H-1PV. Further experiments indicated that CXCL4L1 and CXCL10 interfered with expression of the viral NS1 protein in KS-IMM cells. Our results indicate that the outcome of parvovirus-based delivery of CXCR3 ligands might be tumor cell type dependent and hence it's application must be considered carefully.status: publishe