Immunotherapy of melanoma: a dichotomy in the requirement for IFN-gamma in vaccine-induced antitumor immunity versus adoptive immunotherapy

J Immunol. 2001 Jun 15;166(12):7370-80. doi: 10.4049/jimmunol.166.12.7370.


The mechanism by which tumors are rejected following the adoptive transfer of tumor-specific T cells is not well characterized. Recent work has challenged the requirement for cytotoxicity mediated by either the perforin/granzyme or Fas/Fas ligand pathway in T cell-mediated tumor regression. Many reports, including ours, suggest that tumor-specific production of IFN-gamma is critical for T cell-mediated tumor regression. However, in most of these studies the evidence to support the role for IFN-gamma is only indirect. We have directly examined the requirement for IFN-gamma using IFN-gamma knockout (GKO) mice. The results show an interesting dichotomy in the requirement for IFN-gamma: Antitumor immunity induced by active-specific immunotherapy (vaccination) required IFN-gamma, whereas adoptive immunotherapy did not. In GKO mice vaccination with the GM-CSF gene-modified B16BL6-D5 tumor (D5-G6) failed to induce protective immunity against parental D5 tumor. However, adoptive transfer of effector T cells from GKO mice cured 100% of GKO mice with established pulmonary metastases and induced long term antitumor immunity and depigmentation of skin. Furthermore, in vivo neutralization of IFN-gamma by mAb treatment or adoptive transfer into IFN-gamma receptor knockout mice failed to block the therapeutic efficacy of effector T cells generated from wild-type or perforin knockout mice. Analysis of regressing metastases revealed similar infiltrates of macrophages and granulocytes in both wild-type and GKO mice. These results indicate that in this adoptive immunotherapy model, neither a direct effect on the tumor nor an indirect effect of IFN-gamma through activation of myeloid or lymphoid cells is critical for therapeutic efficacy.

Publication types

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

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / therapeutic use
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Cytotoxicity, Immunologic / genetics
  • Female
  • Immune Sera / administration & dosage
  • Immunohistochemistry
  • Immunophenotyping
  • Immunotherapy, Adoptive* / methods
  • Injections, Intravenous
  • Injections, Subcutaneous
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / deficiency
  • Interferon-gamma / genetics
  • Interferon-gamma / physiology*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Lymphocyte Activation / genetics
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / mortality
  • Melanoma, Experimental / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocyte Subsets / transplantation
  • T-Lymphocytes, Cytotoxic / immunology
  • Th2 Cells / immunology
  • Th2 Cells / metabolism
  • Tumor Cells, Cultured / transplantation
  • Vitiligo / genetics
  • Vitiligo / immunology


  • Cancer Vaccines
  • Cytokines
  • Immune Sera
  • Interferon-gamma