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

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  • Additional Information
    • Source:
      Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Print ISSN: 0021-9738 (Print) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
    • Publication Information:
      Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
      Original Publication: New Haven [etc.] American Society for Clinical Investigation.
    • Subject Terms:
      CD4-Positive T-Lymphocytes/*immunology ; CD40 Antigens/*physiology ; Interleukin-2/*therapeutic use ; Melanoma, Experimental/*therapy ; Membrane Glycoproteins/*physiology; Animals ; Antigen-Presenting Cells/physiology ; CD40 Antigens/genetics ; CD40 Ligand ; Female ; Lymphocyte Activation ; Melanoma, Experimental/immunology ; Membrane Glycoproteins/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout
    • 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.
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    • Grant Information:
      CA-42508 United States CA NCI NIH HHS
    • Accession Number:
      0 (CD40 Antigens)
      0 (Interleukin-2)
      0 (Membrane Glycoproteins)
      147205-72-9 (CD40 Ligand)
    • Publication Date:
      Date Created: 20000607 Date Completed: 20000824 Latest Revision: 20181113
    • Publication Date:
      20221213
    • Accession Number:
      PMC300854
    • Accession Number:
      10.1172/JCI9177
    • Accession Number:
      10841521