Impaired infiltration of tumor-specific cytolytic T cells in the absence of interferon-γ despite their normal maturation in lymphoid organs during CD137 monoclonal antibody therapy

Engagement of CD137 receptor by agonistic monoclonal antibodies (mAb) stimulates IFN-γ production and eradicates established tumors in syngeneic mouse models. Using IFN-γ-deficient mice or neutralizing mAb, we demonstrate that IFN-γ is an absolute requirement for the antitumor effect of CD137 mAb. Despite progressive tumor growth in IFN-γ-depleted mice, a fully competent CD8⁺ cytolytic T cell (CTL) response developed in the lymph nodes. In addition, tumor cell sensitivity to IFN-γ was not required because expression of a dominant-negative IFN-γ receptor on the tumor did not affect the therapeutic effect of CD137 mAb. However, in the absence of IFN-γ, the number of tumor-infiltrating CD8⁺ CTLs was drastically decreased. Our results demonstrate that IFN-γ is a critical factor regulating the infiltration of antigen-specific CTL into the tumor.