Activated macrophages migrate to the subcutaneous tumor site via the peritoneum: A novel route of cell trafficking

Spontaneous regression of AK-5 tumor in syngeneic hosts reported earlier in volves the interplay of Th1-type cytokines and cell-mediated immunity. Upon subcutaneous transplantation of AK-5 cells, there was accumulation of immu ne cells in the peritoneum, of which macrophages were the predominant type and were found to be in a hyperactive state. They released macrophage-deriv ed tumoricidal mediators like NO, O-2(-), and ONOO- which exhibited potent cytotoxic activity against AK-5 cells in vitro. Interestingly, there was a dramatic disappearance of these hyperactive cells from the peritoneal cavit y which correlated well with the onset of tumor regression at the subcutane ous site. Direct labeling of these cells in the peritoneum by the tracking dye PKH26 showed their migration to the tumor site. Similarly, frozen tumor sections when scanned under confocal microscope clearly exhibited fluoresc ent macrophages embedded into the tumor. Immunohistochemical sections of th ese intratumoral macrophages showed nitrotyrosine residues, indicating thei r contribution in the free-radical-mediated AK-5 cell death, thereby leadin g to successful tumor remission. These observations suggest a directional m igration of the hyperactivated peritoneal population to the tumor site. We have also confirmed the influx of macrophages and other immune cells into t he peritoneum after sc transplantation of Meth A tumor cells in Balb/c mice . Our studies suggest a role for the peritoneal compartment in imparting ap propriate stimulus to the immune cells prior to their participation in the antitumor immune response. These studies suggest a novel route of macrophag e trafficking via the peritoneum. (C) 2001 Academic Press.