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Melanoma immunotherapy by targeted IL-2 depends on CD4(+) T-cell help mediated by CD40/CD40L interaction

Academic Article
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Overview

authors

  • Lode, H. N.
  • Xiang, R.
  • Pertl, U.
  • Forster, E.
  • Schoenberger, S. P.
  • Gillies, S. D.
  • Reisfeld, Ralph

publication date

  • June 2000

journal

  • Journal of Clinical Investigation  Journal

abstract

  • The induction of tumor-protective immunity against malignancies remains a major challenge in cancer immunotherapy. A novel, humanized anti-ganglioside-GD(2)-IL-2 immunocytokine (hu14.18-IL-2) induced CD8(+) T cells to eradicate established pulmonary metastases of B78-D14 murine melanoma, in a process that required help by CD4(+) T cells and was mediated by the CD40/CD40 ligand (CD40L) interaction. The anti-tumor effect was diminished in mice deficient in CD4(+) T-cells. Three lines of evidence show that CD4(+) T-cell help was mediated by CD40/CD40L interaction but not by endogenous IL-2 production. First, the hu14.18-IL-2-induced anti-tumor response is partially abrogated in C57BL/6J CD40L knockout (KO) mice in contrast to C57BL/6J IL-2 KO animals, in which the immunocytokine was completely effective. Second, partial abrogation of the anti-tumor effect is induced with anti-CD40L antibodies to the same extent as with CD4(+) T-cell depletion. Third, a complete anti-tumor response induced by hu14.18-IL-2 can be reconstituted in C57BL/6J CD40L KO mice by simultaneous stimulation with an anti-CD40 mAb. These results suggest that help provided by CD4(+) T cells via CD40/CD40L interactions in our tumor model is crucial for effective immunotherapy with an IL-2 immunocytokine.

subject areas

  • Animals
  • Antigen-Presenting Cells
  • Antigens, CD40
  • CD4-Positive T-Lymphocytes
  • CD40 Ligand
  • Female
  • Interleukin-2
  • Lymphocyte Activation
  • Melanoma, Experimental
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
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Identity

PubMed Central ID

  • PMC300854

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/jci9177

PubMed ID

  • 10841521
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Additional Document Info

start page

  • 1623

end page

  • 1630

volume

  • 105

issue

  • 11

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