Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency

IL-15 supports improved antitumor immunity. How to best incorporate IL-15 into vaccine formulations for superior cancer immunotherapy remains a challenge. DC-derived IL-15 (DCIL-15) notably has the capacity to activate DC, to substitute for CD4(+) Th and to potentiate vaccine efficacy making IL-15-based therapies attractive treatment options. We observed in transplantable melanoma, glioma and metastatic breast carcinoma models that DCIL-15-based DNA vaccines in which DC specifically express IL-15 and simultaneously produce tumor Aghsp70 were able to mediate potent therapeutic efficacy that required both host Batf3(+) DC and CD8(+) T cells. In an inducible Braf(V600E)/Pten-driven murine melanoma model, DCIL-15 (not rIL-15)-based DNA vaccines elicited durable therapeutic CD8(+) T cell-dependent antitumor immunity. DCIL-15 was found to be superior to rIL-15 in “licensing” both mouse and human DC, and for activating CD8(+) T cells. Such activation occurred even in the presence of Treg, without a need for CD4(+) Th, but was IL-15/IL-15Rα-dependent. A single low-dose of DCIL-15 (not rIL-15)-based DC vaccines induced therapeutic antitumor immunity. CD14(+) DC emigrating from human skin explants genetically-immunized by IL-15 and Aghsp70 were more effective than similar DC emigrating from the explants genetically-immunized by Aghsp70 in the presence of rIL-15 in expressing membrane-bound IL-15/IL-15Rα and activating CD8(+) T cells. These results support future clinical use of DCIL-15 as a therapeutic agent in battling cancer.