Targeting a mimotope vaccine to activating Fcgamma receptors empowers dendritic cells to prime specific CD8+ T cell responses in tumor-bearing mice.
A major challenge for inducing antitumor immune responses with native or modified tumor/self-Ags in tumor-bearing hosts relates to achieving efficient uptake and processing by dendritic cells (DCs) to activate immune effector cells and limit the generation of regulatory T cell activity. We analyzed the ability of therapeutic DC vaccines expressing a CD166 cross-reactive mimotope of the GD2 ganglioside, 47-LDA, to selectively expand adoptively transferred, tumor-specific T cells in NXS2 neuroblastoma tumor-bearing syngeneic mice. Before the adoptive cell transfer and DC vaccination, the tumor-bearing mice were lymphodepleted by nonmyeloablative total body irradiation or a myeloablative regimen that required bone marrow transplantation. The 47-LDA mimotope was presented to DCs either as a linear polypeptide in conjunction with universal Th epitopes or as a fusion protein with the murine IgG2a Fc fragment (47-LDA-Fcgamma2a) to deliver the antigenic cassette to the activating Fcgamma receptors. We demonstrate that immunization of adoptively transferred T cells in tumor-bearing mice with the 47-LDA mimotope expressed in the context of the activating Fc fusion protein induced higher levels of antitumor immune responses and protection than the 47-LDA polypeptide-DC vaccine. The antitumor efficacy of the therapeutic 47-LDA-Fcgamma2a-DC vaccine was comparable to that achieved by a virotherapy-associated cancer vaccine using a recombinant oncolytic vaccinia virus expressing the 47-LDA-Fcgamma2a fusion protein. The latter treatment, however, did not require total body irradiation or adoptive cell transfer and resulted in induction of antitumor immune responses in the setting of established tolerance, paving the way for testing novel anticancer treatment strategies.
Gil
Margaret
M
Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Bieniasz
Magdalena
M
Wierzbicki
Andrzej
A
Bambach
Barbara J
BJ
Rokita
Hanna
H
Kozbor
Danuta
D
D020410:Activated-Leukocyte Cell Adhesion Molecule / Q000276:immunology* / Q000378:metabolism; D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003713:Dendritic Cells / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D005732:Gangliosides / Q000276:immunology; D053208:Kaplan-Meier Estimate; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D017452:Receptors, IgG / Q000819:agonists / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014916:Whole-Body Irradiation
D020410:Activated-Leukocyte Cell Adhesion Molecule; D019496:Cancer Vaccines; D000939:Epitopes; D005732:Gangliosides; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C019403:ganglioside, GD2