Concomitant immunization by the fully antigenic counterparts prevents modulated tumor cells from escaping cellular immune elimination.

Abstract

In a mathematical model of the cellular antitumor immune response, we studied the possible role of antigenic modulation as a tumor escape mechanism. Modulated tumor cells arise from normal (fully antigenic) tumor cells when the latter interact with antibodies. Modulated tumor cells demodulate when antibody concentrations are sufficiently low. Through modulation, tumor cells become less sensitive to cytotoxic macrophages (cell lysis) and contribute less to the stimulation of the immune system. These experimental data are incorporated in a model which we have analyzed previously. The model incorporates interactions between macrophages and T lymphocytes, which lead to cellular antitumor immune reactions (i.e., to cytotoxic macrophages). Parameters were derived from the immune resistance of DBA/2 mice to the SL2 tumor. Although all parameters were chosen deliberately to favor the modulation process (i.e., modulation proceeds fast, demodulation slowly, and the killing rate is reduced 50-fold), modulation is found to be a poor tumor escape mechanism. Heterogeneous populations of modulated and normal tumor cells are easily rejected. Homogeneous populations of modulated cells do escape, however. We conclude that the impact of modulation as an escape mechanism remains small because modulated tumor cells do not appear until the immune system has been stimulated (immunized) by the fully antigenic tumor cells. Thus, the elimination of modulated tumor cells generally occurs merely as a side effect of the immune response which is directed primarily against the fully antigenic tumor cells. Parameter sensitivity analysis shows that this conclusion holds true only for cellular immunity. Conversely, the parameter analysis suggests that antigenic modulation plays a deleterious role in cytotoxic antibody responses (e.g., monoclonal antibody therapy).