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

J Clin Invest. 2002 Mar;109(5):651-9. doi: 10.1172/JCI14184.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antigens, CD
  • Antigens, Neoplasm / metabolism*
  • Female
  • Humans
  • Immune Tolerance
  • Immunotherapy / methods*
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology*
  • Neoplasms, Experimental / therapy*
  • Oncogene Proteins, Viral / immunology
  • Papillomavirus E7 Proteins
  • Receptors, Nerve Growth Factor / immunology*
  • Receptors, Tumor Necrosis Factor / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antigens, Neoplasm
  • Oncogene Proteins, Viral
  • Papillomavirus E7 Proteins
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • oncogene protein E7, Human papillomavirus type 16