Deletion or Unresponsiveness of Antitumor Effector Cells

In addition to passive defense against the host immune system by minimizing its immu-nogenicity, the tumor also mounts active immune resistance by surface expression or secreting inhibitory/proapoptotic molecules against tumor-specific effector cells.

Secretion of immunosuppressive cytokine transforming growth factor (TGF)-P by numerous tumor types could limit local inflammatory responses and profoundly suppress APC functions, which, in turn, inhibit T-cell activation (19,20).

Overexpression of indoleamine 2,3-dioxygenase (IDO) by a large number of human tumor types has been recently described as a new resistance mechanism (21). T-Cell proliferation is heavily dependent on tryptophan metabolism, and IDO is an enzyme that catalyzes tryptophan degradation. In a mouse model, systematic administration of IDO inhib itors partially reversed the progression of an IDO-positive tumor, indicating a therapeutic value (21).

The T regulatory cell (T-reg), vital for maintaining peripheral tolerance against autoimmunity, has been shown to play a negative role in antitumor immunity (22). Recent evidence suggests that the tumor might utilize the host T-reg cell to suppress immune response. Wang and colleagues identified a tumor antigen-specific CD4+ CD25+ T-reg cell clone generated from human tumor-infiltrating lymphocytes (TILs) and demonstrated that the T-reg clone could strongly suppress T-cell response (23). Depletion of CD25+ T-reg cells with antibodies abrogated the unresponsiveness of CTL to syngeneic tumors in vivo and in vitro and led to regression of various tumors in animal models (24-27). These studies support the T-reg cell as an emerging target for cancer immunotherapy.

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