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 interac ts with the CCR1, CCR1, and CCR3 receptors and has a spectrum of actio n encompassing T cells, NK cells, eosinophils, and dendritic cells (DC ), in addition to mononuclear phagocytes, This broad spectrum of actio n 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 mas tocytoma cells transfected with the gene coding MCP-3 (P815/MCP-3) gre w in syngeneic hosts and underwent rejection. Rejection was associated with profound alterations of leukacyte infiltration and resistance to subsequent challenge with P815 cells, Tumor-associated macrophages, a lready present in copious numbers, T cells, eosinophils, and neutrophi ls, increased in tumor tissues after gene transfer. DC, identified as DEC205(+), high MHC class II+, CD11c(+) cells, did not increase substa ntially in the tumor mass. However, in peritumoral tissues, DC accumul ated in perivascular areas, P815/MCP-3-transfected tumor cells grew no rmally in node mice. Increased accumulation of macrophages and polymor phonuclear 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 retarda tion of MCP-elicited tumor rejection, Thus, MCP-3 gene transfer elicit s tumor rejection by activating type I T cell-dependent immunity. It i s tempting to speculate that altered trafficking of APCs, which expres s receptors and respond to MCP-3, together with recruitment of activat ed T cells, underlies activation of specific immunity by MCP-3-transfe cted cells.