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

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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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.

Original languageEnglish (US)
Pages (from-to)651-659
Number of pages9
JournalJournal of Clinical Investigation
Volume109
Issue number5
DOIs
StatePublished - 2002

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CD137 Antigens
Neoplasms
Neoplasm Antigens
Immunotherapy
Experimental Melanomas
Cytotoxic T-Lymphocytes

ASJC Scopus subject areas

  • Medicine(all)

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Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. / Wilcox, Ryan A.; Flies, Dallas B.; Zhu, Gefeng; Johnson, Aaron J.; Tamada, Koji; Chapoval, Andrei I.; Strome, Scott E.; Pease, Larry R; Chen, Lieping.

In: Journal of Clinical Investigation, Vol. 109, No. 5, 2002, p. 651-659.

Research output: Contribution to journalArticle

Wilcox, Ryan A. ; Flies, Dallas B. ; Zhu, Gefeng ; Johnson, Aaron J. ; Tamada, Koji ; Chapoval, Andrei I. ; Strome, Scott E. ; Pease, Larry R ; Chen, Lieping. / Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. In: Journal of Clinical Investigation. 2002 ; Vol. 109, No. 5. pp. 651-659.
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