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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Article

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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T-cell activation after hu14.18–IL-2 and anti-CD40 therapy of establishe...
T-cell activation after hu14.18–IL-2 and anti-CD40 therapy of established pulmonary melanoma metastases. Increase in the proportion of CD8+ T cells characterized by elevated CD69 and CD25 expression was investigated in mice bearing established pulmonary metastases (resulting from 1.25 × 106 B78-D14 2.34 cells injected intravenously) after therapy with hu14.18–IL-2 and anti-CD40. Treatment was initiated 4 days after tumor-cell inoculation by daily intravenous administration of either 20 μg hu14.18–IL-2 or PBS for 5 days, or a single intraperitoneal injection with 200 μg anti-CD40 mAb. Depletion of CD4+ T cells was accomplished as described in Methods. One group of six mice was not injected with B78-D14 2.34 cells (naive control). Four days after completion of the treatment, mice were euthanized, and splenocytes were subjected to FACS® analysis for CD69/CD8 and CD25/CD8 double-positive T cells. Bars represent mean and SD of five mice per group. Findings between experimental groups and all control groups were statistically significant (AP < 0.05, BP < 0.01, CP < 0.001).