Melanoma immunotherapy by targeted IL-2 depends on CD4+ T-cell help mediated by CD40/CD40L interaction
Holger N. Lode, … , Stephen D. Gillies, Ralph A. Reisfeld
Holger N. Lode, … , Stephen D. Gillies, Ralph A. Reisfeld
Published June 1, 2000
Citation Information: J Clin Invest. 2000;105(11):1623-1630. https://doi.org/10.1172/JCI9177.
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Melanoma immunotherapy by targeted IL-2 depends on CD4+ T-cell help mediated by CD40/CD40L interaction

Abstract

The induction of tumor-protective immunity against malignancies remains a major challenge in cancer immunotherapy. A novel, humanized anti-ganglioside-GD2–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.

Authors

Holger N. Lode, Rong Xiang, Ursula Pertl, Elisabeth Förster, Stephen P. Schoenberger, Stephen D. Gillies, Ralph A. Reisfeld

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Activation of APCs by administration of hu14.18–IL-2 and anti-CD40 in me...
Activation of APCs by administration of hu14.18–IL-2 and anti-CD40 in melanoma metastases–bearing mice. APC activation as defined by upregulation of B7-2 and MHC class II molecules was determined in mice with established pulmonary metastases (resulting from 1.25 × 106 B78-D14 2.34 cells injected intravenously) after hu14.18–IL-2 and anti-CD40 therapy, compared with that of naive mice. Treatment was initiated 4 days after tumor-cell inoculation by daily intravenous administrations of 20 μg hu14.18–IL-2 for 5 days, or a single intraperitoneal injection with either 200 μg anti-CD40 mAb or PBS. Depletion of CD4+ T cells was accomplished as described in Methods. Four days after completion of the treatment, mice were euthanized and splenocytes were subjected to FACS® analysis for CD11c/B7-2 (open bars) and CD11c/MHC class II I-Ab (closed bars) double-positive APCs. Values were expressed as percentage of values from naive controls. Bars represent mean and SD of four mice per group. Findings between experimental groups and all control groups were statistically significant (AP < 0.02, BP < 0.01, CP < 0.0005, DP < 0.02).