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Anti-4-1BB Monoclonal Antibody Enhances Rejection of Large Tumor Burden by Promoting Survival but not Clonal Expansion of Tumor-specific CD8⁺ T Cells¹

Division of Cancer Immunology, Department of Pathology and Comprehensive Cancer Center, Ohio State University Medical Center, Columbus, Ohio 43210 [K. F. M., P. Z., Y. L.], and Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905 [L. C.]

Anti-4-1BB monoclonal antibody (mAb) has been shown to induce antitumor immunity by a CD4/CD8-dependent mechanism, but its direct effect on tumor-specific CD8⁺ T cells in tumor rejection is unclear. Here we used transgenic CD8⁺ T cells against the unmutated tumor rejection antigen P1A to analyze whether this mAb can promote CD8⁺ T-cell function against large tumors in the absence of CD4⁺ T-helper cells. RAG-2(-/-) mice were challenged with P1A-expressing plasmacytoma J558. Once tumor size reached a diameter of 0.85–1.75 cm, mice were treated with P1A-specific CD8⁺ CTL (P1CTL) in conjunction with anti-4-1BB mAb or control IgG. All of the mice showed a partial regression of tumor, but mice treated with anti-4-1BB mAb exhibited markedly enhanced tumor rejection, delayed tumor progression, and prolonged survival. Correspondingly, we observed a substantial increase in the number of P1CTL in anti-4-1BB mAb-treated mice. Surprisingly, anti-4-1BB mAb did not accelerate division of the tumor-specific CD8⁺ T cells, and the increase in tumor-specific T-cell number was due to reduced activation-induced cell death. These results indicate that anti-4-1BB mAb can promote CD8⁺ T cell-mediated protection against large tumors in the absence of CD4⁺ T-cell help by promoting P1CTL survival without increasing initial clonal expansion.

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