Suggestions On Strategies To Break Dominant Tolerance To Cancer Cells

How can we then achieve effective anti-tumor immunity, while avoiding the risk of emergence of autoimmune diseases? The experimental protocols, which make normal animals suffer from autoimmune disease, seem to give us a clue to approach the problem.

It has been shown that treatment of normal adult animals with cyclophosphamide (Cy) or sublethal y-irradiation, if coupled with thymectomy, results in development of various organ-specific autoimmune disease, whereas each treatment alone does not induce any disease [28, 29], It has been suggested that this drastic effect of Cy and y-irradiation is due to elimination of regulatory T cell pool from the periphery. Obviously, if the animals are not thymectomized, the pool is eventually restored by thymic emigrants and consequently the animals are free of any autoimmune disease [1,2, 28, 29]. In addition, it is also shown that repetitive infusion of anti-CD25 monoclonal antibody to normal mice lead to emergence of organ-specific autoimmune disease [30]. Increasing numbers of evidence have shown that regulatory T cells are enriched in CD25+ CD4 T cells in normal mice, which constitute rare population in the periphery (5-10% of CD4 T cells in the spleen and the lymph nodes) [31-35]. Thus, repetitive infusion of anti-CD25 antibody results in specific depletion of such regulatory T cells [30],

The above observations indicate that one can transiently eliminate regulatory T cells by these treatments without emergence of any autoimmune disease, although it is not clear that reduced number of anti-CD25 antibody infusion can do the task. Therefore, it could be expected that temporary depletion of reg ulatory T cells by such treatments should shift the balance between tolerance and destructive immune response against tumor cells to the latter, if followed by adoptive transfer of anti-tumor effector T cells. Alternatively, active vaccination with tumor cells or antigens together with inflammatory cytokines, such as IFN-y or IL-12, could be substituted for the transfer of effector T cells, for such molecules are expected to effectively prime recent thymic emigrants into inflammatory phenotypes in the absence of regulatory T cells.

A series of experiments by North strongly support this idea by demonstrating that treatment of tumor-bearing mice with Cy or sublethal y-irradiation can lead to complete regression of various established tumor, if combined with transfer of tumor-sensitized effector T cells. They have shown that the effect of Cy or y-irradiation is not due to direct cytotoxicity against tumor cells but to elimination of CD4 "suppressor" T cells. Thus, these treatments alone do not induce tumor regression, and co-transfer of peripheral CD4 T cells from tumor-bearing mice inhibits tumor regression [36-39]. In addition, it is also demonstrated that treatment with Cy together with IL-12 can cause complete eradication of established tumors, further supporting the idea [40].

These observations clearly show that Cy or sublethal y -irradiation treatments, if combined with further immune manipulations, are indeed appropriate therapeutic approaches for cancer immunotherapy, precisely because they contribute to removal of dominant regulatory mechanisms. However, considering non-specific cytotoxic effects induced by Cy and y-irradiation, treatments that specifically deplete regulatory T cells, such as infusion of anti-CD25 antibody, are apparently much preferable. Development of cytotoxic or suppressive drugs specifically targeted to regulatory T cells should facilitate development of better strategies for cancer immunotherapy.

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