Dendritic cell-derived interleukin-15 is crucial for therapeutic cancer vaccine potency.
IL-15supports improved antitumor immunity. How to best incorporateIL-15into 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 expressIL-15and simultaneously produce tumorAghsp70were able to mediate potent therapeutic efficacy that required both host Batf3+DC and CD8+T cells. In an inducible BrafV600E/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 byIL-15andAghsp70were more effective than similar DC emigrating from the explants genetically-immunized byAghsp70in 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.
Department of Dermatology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA.
Yi
Y
Zhang
Department of Dermatology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA.
Shenghe
S
Tian
Department of Dermatology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA.
Zuqiang
Z
Liu
Department of Dermatology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA.
Jiying
J
Zhang
Lymphoid Malignancies Branch; Center for Cancer Research, National Cancer Institute ; Bethesda, MD USA.
Meili
M
Zhang
Departments of Dermatology and Pathology; Yale University School of Medicine ; New Haven, CT USA.
Marcus W
MW
Bosenberg
Department of Immunology and Microbiology; University of Colorado ; Aurora, CO USA.
Ross M
RM
Kedl
Lymphoid Malignancies Branch; Center for Cancer Research, National Cancer Institute ; Bethesda, MD USA.
Thomas A
TA
Waldmann
Department of Dermatology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA ; Department of Immunology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute ; Pittsburgh, PA USA.
Walter J
WJ
Storkus
Department of Dermatology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA ; Department of Immunology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute ; Pittsburgh, PA USA.
Louis D
LD
Falo
Department of Dermatology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA ; Department of Immunology; University of Pittsburgh School of Medicine ; Pittsburgh, PA USA ; University of Pittsburgh Cancer Institute ; Pittsburgh, PA USA.
Zhaoyang
Z
You
DC; IL-15; cancer vaccines