Breaking down the walls of immunological ignorance

T cells that respond to an antigen challenge in vitro but fail to do so in a living animal are said to be in a state of immunological ignorance. Chen and his colleagues have argued for some time that this poorly understood state can help explain the workings and, crucially, the failings of immunological surveillance for tumors. Ignorance of tumor antigens has been ascribed to the lack of costimulatory signals, and it appears that one strategy of immune evasion by tumors is the down regulation of otherwise common costimulatory activators. Still, some experimentally induced tumors, expressing known tumor antigens that are targeted by defined CTL clones, can be eliminated when T cells are provided an additional, costimulatory signal. In their current report, Wilcox et al. develop a useful reagent for this purpose, and they show that such a co-stimulatory treatment is not always sufficient to induce tumor regression. The authors injected a monoclonal antibody to the costimulatory mediator CD137, a T cell?borne relative of the TNF receptor. This novel agonistic antibody stimulates the expansion and activation of the necessary CTL clone, allowing animals with one type of carcinoma undergo a dramatic tumor regression following treatment. Interestingly, another tumor type, a thymoma that displays the same tumor antigen, is refractory to this treatment, indicating that the CTLs remain ignorant of the antigen when it occurs in the latter context. Wilcox et al. find that this ignorant state can be overcome when the animals are provided not just the agonistic antibody, but also an antigenic peptide recognized by the tumor-specific CTL. Hence, they argue that either inadequate levels of the presented antigen or insufficient costimulatory signaling through CD137 can lead to immunological ignorance and allow tumor growth to proceed unchecked. Providing one or both of these signals might therefore heighten the efficiency of tumor surveillance in animals with spontaneous tumors as well.

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