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Impaired Infiltration of Tumor-specific Cytolytic T Cells in the Absence of Interferon- despite Their Normal Maturation in Lymphoid Organs during CD137 Monoclonal Antibody Therapy¹

Departments of Immunology [R. A. W., D. B. F., K. T., A. J. J., L. R. P., M. R., L. C.] and Neurology [A. J. J., M. R.], Mayo Graduate and Medical Schools, Mayo Clinic, Rochester, Minnesota 55905; Shanghai International Cancer Institute, Shanghai 200433, China [H. W., Y. G., L. C.]; and Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, Nebraska 68198 [Y. G.]

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

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