Identification of immune factors regulating antitumor immunity using polymeric vaccines with multiple adjuvants.
The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study, we used polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, to identify dendritic cell (DC) subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of granulocyte macrophage colony-stimulating factor (GM-CSF) and various Toll-like receptor (TLR) agonists affected 70% to 90% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (≤40 mm(2)), resulting in 33% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs, plasmacytoid DCs (pDC), along with local interleukin (IL)-12, and granulocyte colony-stimulating factor (G-CSF) concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Furthermore, vaccine studies in Batf3(-/-) mice revealed that CD8(+) DCs are required to affect tumor protection, as vaccines in these mice were deficient in cytotoxic T lymphocytes priming and IL-12 induction in comparison with wild-type. These studies broadly demonstrate that three-dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, pDCs, IL-12, and G-CSF play important roles in priming effective antitumor responses with these vaccines.
Authors' Affiliations: Wyss Institute for Biologically Inspired Engineering, Harvard University; Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; and Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts.
Omar A
OA
Ali
Catia
C
Verbeke
Chris
C
Johnson
R Warren
RW
Sands
Sarah A
SA
Lewin
Des
D
White
Edward
E
Doherty
Glenn
G
Dranoff
David J
DJ
Mooney
D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations; D003713:Dendritic Cells / Q000276:immunology; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018664:Interleukin-12 / Q000378:metabolism; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D011070:Poly I-C / Q000008:administration & dosage; D011098:Polyglactin 910 / Q000008:administration & dosage; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008050:Lipid A; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D018664:Interleukin-12; D011098:Polyglactin 910; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C048436:monophosphoryl lipid A; D011070:Poly I-C