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Both cytolytic T-lymphocytes and cytolytic macrophages have been implicated in the long-term maintenance of L5178Y cells in a tumor-dormant state in DBA/2 mice. Eventually, however, the tumor-dormant state terminates, and all mice develop ascitic tumors. In an evaluation of the mechanisms involved in termination of the tumor-dormant state, we detected in the peritoneal cavity of many tumor-dormant mice macrophages with increased capacity to suppress the in vitro generation of a secondary anti-L5178Y cell cytolytic T-lymphocyte response. The incidence of macrophage-mediated immunosuppressive activity in individual tumor-dormant mice was related directly to the number of tumor cells in the peritoneal cavity of those mice. Furthermore, in tumor-dormant mice harboring fewer than 5 X 10(4) L5178Y cells, the detection of macrophage-mediated immunosuppressive activity was a prognostic indicator of termination of the tumor-dormant state and development of an ascitic tumor. These data suggest that peritoneal macrophage-mediated immunosuppressive activity, through inhibition of cytolytic T-lymphocyte generation in vivo, contributes to the termination of the tumor-dormant state and development of ascitic tumors.

The L5178Y-cell tumor dormant state in DBA/2 mice is an excellent model for assessing immunologically mediated tumor-growth restraint mechanisms associated with establishment and control of a tumor dormant state. It has enabled us to relate components of the host's tumor suppressive immune system to the stage of tumor dormancy and the magnitude of the tumor burden. A strong CTL response has been associated with establishment of the tumor dormant state and can be reelicited in vivo or in vitro, after its initial decline, by reexposure to tumor antigen. This reelicitation is mediated via immunologic stimulation of memory CTL. Combined cultures of NAD T-lineage lymphocytes and macrophages from tumor dormant mice produce considerable cytolytic activity where little or no activity can be detected in the individual populations. Based on the similar pattern of tumor target cell specificity of the two responses, it is likely that memory CTL contribute to this synergistic cytolytic activity. The synergistic cytolytic response persists after CTL activity has waned to undetectable levels and is probably the predominant cytolytic activity associated with maintenance of the tumor dormant state. However, this activity may be obscured by proliferation of endogenous tumor cells, which in turn triggers direct macrophage-mediated cytolytic activity. The target cell specificity of this direct macrophage-mediated cytolytic response is also similar to the CTL response suggesting T cell (or memory CTL) involvement in its generation. The L5178Y-cell tumor dormant model is well suited for attempts at cure with immunotherapy. Active specific and nonspecific immunotherapy are each capable of eliminating all tumor cells from approximately 50% of tumor dormant mice. The L5178Y-cell tumor dormant state is one of several animal models of tumor dormancy. The great variety of growth restraint mechanisms that control tumor dormant states in animal systems is strong evidence that tumor dormant states exist in cancer in human beings.

Cytolytic T-lymphocytes (CTL) can be repeatedly stimulated in L5178Y cell tumor-dormant DBA/2 mice by the i.p. inoculation of 2 X 10(6) X-irradiated L5178Y cells. The restimulated CTL activity has the same kinetics of generation and decline and the same target cell specificity as does the CTL response generated during establishment of the L5178Y cell tumor dormant state. No increase in adherent cell-mediated cytolytic activity or cytolytic or cytophilic anti-L5178Y antibody can be detected after inoculation of irradiated L5178Y cells. The repeated stimulation of CTL activity in tumor-dormant DBA/2 mice results in the elimination of L5178Y cells from a significant number of tumor-dormant mice.