MCP-3 (CCL7) delivered by parvovirus MVMp reduces tumorigenicity of mouse melanoma cells through activation of T lymphocytes and NK cells.
Monocyte chemotactic protein 3 (MCP-3/CCL7), a CC chemokine able to attract and activate a large panel of leukocytes including natural killer cells and T lymphocytes, could be beneficial in antitumor therapy. Vectors were constructed based on the autonomous parvovirus minute virus of mice (MVMp), carrying the human (MCP-3) cDNA. These vectors were subsequently evaluated in the poorly immunogenic mouse melanoma model B78/H1. The infection of the tumor cells with MCP3-transducing vector at low virus input multiplicities, but not with wild-type virus, strongly inhibited tumor growth after implantation in euthymic mice. In a therapeutic B78/H1 model, repeated intratumoral injections of MCP3-tranducing virus prevented further tumor expansion as long as the treatment was pursued. The antitumor effects of the MCP-3-transducing vector were not restricted to this tumor model since they could also be observed in the K1735 melanoma. The depletion of CD4, CD8, NK cells and of interferon gamma (IFNgamma) in mice implanted with MVMp/MCP3-infected B78/H1 cells abolished the antitumor activity of the vector. The latter data, together with tumor growth in nude mice and reverse-transcriptase (RT)-PCR analyses of MVMp/MCP3-treated tumors, clearly showed that activated CD4, CD8 and NK cells were indispensable for the antineoplastic effect in the B78/H1 tumor. Altogether, our results show that MCP3-transducing parvovirus vectors may be quite potent against poorly or nonimmunogenic tumors, even in conditions where only a fraction of the tumor cell population is efficiently infected with recombinant parvoviruses.
Wetzel
Kristiane
K
Infection and Cancer Program, Abteilung F010, and Institut National de la Santé et de la Recherche Médicale U701, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, D-69120 Heidelberg, Germany.
Struyf
Sofie
S
Van Damme
Jo
J
Kayser
Tim
T
Vecchi
Annunciata
A
Sozzani
Silvano
S
Rommelaere
Jean
J
Cornelis
Jan J
JJ
Dinsart
Christiane
C
D000818:Animals; D049109:Cell Proliferation; D054410:Chemokine CCL7; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D053804:Granzymes / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008915:Minute Virus of Mice / Q000235:genetics; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics*; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics; D012878:Skin Neoplasms / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*
C515450:CCL7 protein, human; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D018945:Monocyte Chemoattractant Proteins; D052899:Pore Forming Cytotoxic Proteins; C483886:perforin, mouse; D007371:Interferon-gamma; D053804:Granzymes