Impaired infiltration of tumor-specific cytolytic T cells in the absence of interferon-gamma despite their normal maturation in lymphoid organs during CD137 monoclonal antibody therapy

Cancer Res. 2002 Aug 1;62(15):4413-8.

Abstract

Engagement of CD137 receptor by agonistic monoclonal antibodies (mAb) stimulates IFN-gamma production and eradicates established tumors in syngeneic mouse models. Using IFN-gamma-deficient mice or neutralizing mAb, we demonstrate that IFN-gamma is an absolute requirement for the antitumor effect of CD137 mAb. Despite progressive tumor growth in IFN-gamma-depleted mice, a fully competent CD8(+) cytolytic T cell (CTL) response developed in the lymph nodes. In addition, tumor cell sensitivity to IFN-gamma was not required because expression of a dominant-negative IFN-gamma receptor on the tumor did not affect the therapeutic effect of CD137 mAb. However, in the absence of IFN-gamma, the number of tumor-infiltrating CD8(+) CTLs was drastically decreased. Our results demonstrate that IFN-gamma is a critical factor regulating the infiltration of antigen-specific CTL into the tumor.

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 / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antigens, CD
  • Cell Line, Transformed
  • DNA-Binding Proteins*
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Interferon-gamma / immunology*
  • Lymph Nodes / immunology*
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy
  • Oncogene Proteins, Viral / immunology
  • Receptors, Nerve Growth Factor / immunology*
  • Receptors, Tumor Necrosis Factor / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • DNA-Binding Proteins
  • E7 protein, Human papillomavirus type 18
  • Epitopes, T-Lymphocyte
  • Oncogene Proteins, Viral
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • TNFRSF9 protein, human
  • Tnfrsf9 protein, mouse
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Interferon-gamma