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 peptide-immunized mice. Mice were injec...
Frequency of E7-specific CTLs in peptide-immunized mice. Mice were injected subcutaneously with 1 × 106 C3 cells. Seven days later, tumor-bearing mice (a) or naive mice (b) were immunized intradermally on the contralateral flank with 50 μg of E7 (aa 49–57) peptide emulsified in IFA (Sigma Chemical Co.). Ab’s including the control rat IgG and mAb 2A (100 μg) were given intraperitoneally in 0.5 ml PBS on days 1 and 4. Cells from two to three mice in each group were pooled. Seven days later, LN cells draining the site of immunization were stained with H-2Db–E7 following in vitro restimulation with irradiated C3 cells, as previously described. (c) After the 4-day restimulation, cells from the draining LNs of the naive mice immunized with E7 peptide and given control rat IgG (filled circles) or mAb 2A (open circles) were used as effectors in a 4-hour 51Cr release assay against EL4 (left panel), E7 peptide–pulsed EL4 (middle panel), and C3 (right panel) targets at the indicated E/T ratios. Data shown is representative of at least four experiments.