Modifying dendritic cells via protein transfer for antitumor therapeutics.
OBJECTIVE
The modification of therapeutic dendritic cells (DC) with various immunostimulatory molecules represents a useful means for improving the antitumor efficacy of DC transfer-based immunotherapy. We have evaluated the feasibility of modifying therapeutic DCs with multiple immunostimulatory molecules using a time-efficient, protein transfer (or protein "painting")-based method.


METHODS
Bone marrow-derived DCs were painted with either control protein human IgG (hIgG) or three immunostimulatory molecules, SLC, 4-1BBL, and TRANCE (the triad protein). Painted DCs were injected intratumorally into mice bearing established tumors. Subsequently, the capacities of painted DCs to migrate to the draining lymph nodes, recruit the host T cells, promote Th1 cytokine responses, and elicit therapeutic antitumor responses were evaluated.


RESULTS
The triad protein transfer yields a uniform population of DCs that coexpress all three of the proteins. Compared with the hIgG-painted DCs, the triad protein-painted DCs migrate more efficiently to the draining lymph nodes and show enhanced capabilities to induce T cell infiltration of tumors and to promote Th1 cytokine responses in vivo. Furthermore, in both the EG.7 and TRAMP-C2 tumor models, compared with the DCs painted with hIgG or only one of the three proteins, the triad protein-painted DCs, upon adoptive transfer, elicit stronger therapeutic responses against established tumors. Importantly, the antitumor responses of the triad protein-painted DCs are mediated by systemic antitumor immunity.


CONCLUSIONS
This study establishes, for the first time, the feasibility of optimizing DC transfer-based immunotherapy via combinatorial protein transfer of therapeutic DCs with an array of immunostimulatory molecules.
Liu
Shanrong
S
Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois 61107, USA.
Foster
Barbara A
BA
Chen
Tie
T
Zheng
Guoxing
G
Chen
Aoshuang
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D019496:Cancer Vaccines; D017690:Cell Transplantation; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D005452:Fluoresceins / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000295:instrumentation* / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013388:Succinimides / Q000494:pharmacology; D018417:Th1 Cells / Q000378:metabolism; D013997:Time Factors
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D005452:Fluoresceins; D007074:Immunoglobulin G; D013388:Succinimides