Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors
Ryan A. Wilcox, … , Larry R. Pease, Lieping Chen
Ryan A. Wilcox, … , Larry R. Pease, Lieping Chen
Published March 1, 2002
Citation Information: J Clin Invest. 2002;109(5):651-659. https://doi.org/10.1172/JCI14184.
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Article Immunology

Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors

Abstract

Treatment of advanced, poorly immunogenic tumors in animal models, considered the closest simulation available thus far for conditions observed in cancer patients, remains a major challenge for cancer immunotherapy. We reported previously that established tumors in mice receiving an agonistic mAb to the T cell costimulatory molecule 4-1BB (CD137) regress due to enhanced tumor antigen–specific cytotoxic T lymphocyte responses. In this study, we demonstrate that several poorly immunogenic tumors, including C3 tumor, TC-1 lung carcinoma, and B16-F10 melanoma, once established as solid tumors or metastases, are refractory to treatment by anti–4-1BB mAb. We provide evidence that immunological ignorance, rather than anergy or deletion, of tumor antigen–specific CTLs during the progressive growth of tumors prevents costimulation by anti–4-1BB mAb. Breaking CTL ignorance by immunization with a tumor antigen–derived peptide, although insufficient to stimulate a curative CTL response, is necessary for anti–4-1BB mAb to induce a CTL response leading to the regression of established tumors. Our results suggest a new approach for immunotherapy of human cancers.

Authors

Ryan A. Wilcox, Dallas B. Flies, Gefeng Zhu, Aaron J. Johnson, Koji Tamada, Andrei I. Chapoval, Scott E. Strome, Larry R. Pease, Lieping Chen

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Frequency of E7-specific CTLs in the TDLNs of C3- and EL4E7-bearing mice...
Frequency of E7-specific CTLs in the TDLNs of C3- and EL4E7-bearing mice. TDLNs were harvested from tumor-bearing mice and restimulated in vitro as described in Figure 3 legend. After 4 days in culture, cells were double-stained with tetrameric H-2Db–E7 or H-2Db–Vp2 (aa 121–130) and anti-CD8. The percentage of total CD8+ cells that stained with the H-2Db–E7 tetramer is shown (a). Viable CD8+ cells were gated, and the fraction of cells that stained with tetrameric H-2Db–E7 (aa 49–57) is shown. Data are presented as the average of three independent experiments (b). Background staining with the H-2Db–Vp2 tetramer was subtracted from the original data.