Reduced tumorigenicity and augmented leukocyte infiltration after monocyte chemotactic protein-3 (MCP-3) gene transfer: perivascular accumulation of dendritic cells in peritumoral tissue and neutrophil recruitment within the tumor.
Monocyte chemotactic protein-3 (MCP-3) is a C-C chemokine that interacts with the CCR1, CCR2, and CCR3 receptors and has a spectrum of action encompassing T cells, NK cells, eosinophils, and dendritic cells (DC), in addition to mononuclear phagocytes. This broad spectrum of action prompted the present study aimed at assessing the antitumor activity of MCP-3 in a gene transfer approach and at providing information as to the actual in vivo leukocyte recruiting capacity of MCP-3. P815 mastocytoma cells transfected with the gene coding MCP-3 (P815/MCP-3) grew in syngeneic hosts and underwent rejection. Rejection was associated with profound alterations of leukocyte infiltration and resistance to subsequent challenge with P815 cells. Tumor-associated macrophages, already present in copious numbers, T cells, eosinophils, and neutrophils, increased in tumor tissues after gene transfer. DC, identified as DEC205+, high MHC class II+, CD11c+ cells, did not increase substantially in the tumor mass. However, in peritumoral tissues, DC accumulated in perivascular areas. P815/MCP-3-transfected tumor cells grew normally in nude mice. Increased accumulation of macrophages and polymorphonuclear neutrophils was evident also in nude mice. mAb against CD4, CD8, and IFN-gamma, but not against IL-4, inhibited rejection of MCP-3-producing cells. An anti-polymorphonuclear mAb caused only a retardation of MCP-3-elicited tumor rejection. Thus, MCP-3 gene transfer elicits tumor rejection by activating type I T cell-dependent immunity. It is tempting to speculate that altered trafficking of APCs, which express receptors and respond to MCP-3, together with recruitment of activated T cells, underlies activation of specific immunity by MCP-3-transfected cells.
Fioretti
F
F
Istituto Ricerche Farmacologiche Mario Negri, Milan, Italy.
Fradelizi
D
D
Stoppacciaro
A
A
Ramponi
S
S
Ruco
L
L
Minty
A
A
Sozzani
S
S
Garlanda
C
C
Vecchi
A
A
Mantovani
A
A
D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054410:Chemokine CCL7; D016207:Cytokines; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D018014:Gene Transfer Techniques; D006084:Graft Rejection / Q000235:genetics; D007113:Immunity, Innate; D007962:Leukocytes / Q000276:immunology*; D008297:Male; D012515:Mast-Cell Sarcoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D018945:Monocyte Chemoattractant Proteins / Q000235:genetics*; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D014162:Transfection / Q000276:immunology
C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins