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

The induction of tumor-protective immunity against malignancies remains a m ajor challenge in cancer immunotherapy. A novel, humanized anti-ganglioside -GD(2)-IL-2 immunocytokine (hu14.18-IL-2) induced CD8(+) T cells to eradica te established pulmonary metastases of B78-D14 murine melanoma, in a proces s that required help by CD4(+) T cells and was mediated by the CD40/CD40 li gand (CD40L) interaction. The anti-tumor effect was diminished in mice defi cient in CD4(+) T-cells. Three lines of evidence show that CD4(+) T-cell he lp was mediated by CD40/CD40L interaction but not by endogenous IL-2 produc tion. First, the hu14.18-IL-2-induced anti-tumor response is partially abro gated in C57BL/GJ CD40L knockout (KO) mice in contrast to C57BL/GJ IL-2 KO animals, in which the immunocytokine was completely effective. Second, part ial abrogation of the anti-tumor effect is induced with anti-CD40L antibodi es to the same extent as with CD4(+) T-cell depletion. Third, a complete an ti-tumor response induced by hu14.18-IL-2 can be reconstituted in C57BL/GJ CD40L KO mice by simultaneous stimulation with an anti-CD40 mAb. These resu lts suggest that help provided by CD4(+) T cells via CD40/CD40L interaction s in our tumor model is crucial for effective immunotherapy with an IL-2 im munocytokine.