Transduction of human MCP-3 by a parvoviral vector induces leukocyte infiltration and reduces growth of human cervical carcinoma cell xenografts.
BACKGROUND
The oncosuppressive properties of some autonomous parvoviruses such as H-1 virus, together with their low pathogenicity, make them attractive vectors for tumor-directed gene therapy. Indeed, it was recently shown that these viruses became endowed with an enhanced oncosuppressive activity after they had been engineered to deliver a recognized therapeutic transgene. This prompted us to use a parvoviral vector to analyse the antineoplastic capacity of MCP-3 (monocyte chemotactic protein-3), a CC chemokine which has a broad spectrum of target cells, and can thus be considered to be a promising candidate for cancer treatment.


METHODS
We explored the use of a parvovirus H-1-based vector encoding human MCP-3 for its antitumor potential on human cervical carcinoma cells. HeLa cells were infected in vitro with the recombinant virus hH1/MCP-3 at a low multiplicity [1 replication unit (RU)/cell] and we investigated the effect of parvovirus-mediated MCP-3 transduction on tumor formation and growth upon implantation of HeLa cells in nude mice.


RESULTS
Infection of HeLa cells with hH1/MCP-3 led to secretion of high levels of MCP-3 and to significant retardation of tumor growth in recipient mice, as compared with HeLa cells that were either buffer-treated or infected with a MCP-3-free vector. Tumors from hH1/MCP-3-infected HeLa cells were heavily infiltrated with activated macrophages and showed increased numbers of dendritic cells. In addition, activated natural killer (NK) cells were also recruited into MCP-3-transduced tumors.


CONCLUSIONS
These observations indicate that parvovirus H-1-transduced MCP-3 is able to exert a significant antitumor activity which is mediated, at least in part, through macrophages and NK cells, under conditions in which activated T cells are lacking.
Wetzel
K
K
Applied Tumor Virology, AbtF0100 INSERM U375, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
Menten
P
P
Opdënakker
G
G
Van Damme
J
J
Gröne
H J
HJ
Giese
N
N
Vecchi
A
A
Sozzani
S
S
Cornelis
J J
JJ
Rommelaere
J
J
Dinsart
C
C
D000818:Animals; D054410:Chemokine CCL7; D016207:Cytokines; D005260:Female; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics* / Q000493:pharmacokinetics / Q000627:therapeutic use; D017992:Parvovirus / Q000235:genetics*; D010957:Plasmids; D011994:Recombinant Proteins / Q000032:analysis; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D002583:Uterine Cervical Neoplasms / Q000628:therapy*
C515450:CCL7 protein, human; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D011994:Recombinant Proteins