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

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