Mechanism Of Action Of Enhanced Antibody Dependent Cellular Cytotoxicity In A Mammary Tumor Model System

Balb/c mice bearing mammary tumors induced by 7,12-dimethylbenzanthracene show enhanced antibody dependent cellular cytotoxicity (ADCC) which increases paralleling tumor growth. Depletion of macrophages from mouse spleen cells on Sephadex G-10 columns resulted in background levels of (\u2751)Cr release in normal mice, whereas tumor bearing mice had a decrease from 81% to 55% in the percent chromium release. Separation of splenocytes from normal and tumor bearers on nylon wool columns resulted in elevated levels in both nylon adherent and nylon nonadherent lymphocytes from tumor bearing mice. Fluorescent activated cell sorting of the nylon adherent cells, based on the presence of surface immunoglobulin (SIg) on their surfaces, demonstrated that both SIg negative as well as the SIg positive cells of mammary tumor bearers were capable of functioning in ADCC. Nylon wool separated spleen cells from normal mice could not exert cytotoxicity against the antibody coated chicken red blood cells.The levels of IgG Fc receptor bearing cells are increased in tumor bearers, but this increase is restricted to the nylon nonadherent population. Thus, the enhanced levels of ADCC obtained in the nylon adherent lymphocytes could be due to an increase in the density of Fc receptors per cell or to an abnormal distribution of this receptor. A modified single cell agarose assay revealed that binding ability of the nylon adherent cells to target cells via the FcR differs between the tumor and normal lymphocyte populations. A greater number of chicken red blood cells were found to bind to the tumor bearers\u27 nylon adherent cells than to the normal counterparts. Binding of (\u27125)I radiolabeled immune complexes and (\u27125)I labeled heat aggregated immunoglobulin again resulted in greater binding in the tumor bearing mice. Analysis of the distribution of fluorescent immune complexes (IC) at the surface of the nylon adherent cells revealed that while in the normal mice these cells readily demonstrate capping function, the majority of the total fluorescent cells from tumor bearers showed patched fluorescence. SIg and concanavalin A (Con A) capping resulted in no altered distribution pattern in the splenocytes from tumor bearing mice, thus suggesting a block in the transmembrane signal, interrupting the normal receptor redistribution that occurs under capping conditions. . . . (Author\u27s abstract exceeds stipulated maximum length. Discontinued here with permission of author.) UM