title: Inflammatory cytokines presented from polymer matrices differentially generate and activate DCsin situ.
abstract: During infection, inflammatory cytokines mobilize and activate dendritic cells (DCs), which are essential for efficacious T cell priming and immune responses that clear the infection. Here we designed macroporous poly(lactide-co-glycolide) (PLG) matrices to release the inflammatory cytokines GM-CSF, Flt3L and CCL20, in order to mimic infection-induced DC recruitment. We then tested the ability of these infection mimics to function as cancer vaccines via induction of specific, anti-tumor T cell responses. All vaccine systems tested were able to confer specific anti-tumor T cell responses and longterm survival in a therapeutic, B16-F10 melanoma model. However, GM-CSF and Flt3L vaccines resulted in similar survival rates, and outperformed CCL20 loaded scaffolds, even though they had differential effects on DC recruitment and generation. GM-CSF signaling was identified as the most potent chemotactic factor for conventional DCs and significantly enhanced surface expression of MHC(II) and CD86(+), which are utilized for priming T cell immunity. In contrast, Flt3L vaccines led to greater numbers of plasmacytoid DCs (pDCs), correlating with increased levels of T cell priming cytokines that amplify T cell responses. These results demonstrate that 3D polymer matrices modified to present inflammatory cytokines may be utilized to effectively mobilize and activate different DC subsetsin vivofor immunotherapy.
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Ali
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA ; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA.
authors.forename: Prakriti
authors.initials: P
authors.lastname: Tayalia
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA ; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Shvartsman
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lewin
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA ; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mooney