Induction of protective cytotoxic T-cell responses by a B-cell-based cellular vaccine requires stable expression of antigen.
B-cell-based cellular vaccines represent a promising approach to active immunotherapy of cancer complementing the use of dendritic cells, especially in pediatric patients and patients with low bone marrow reserves. B cells can be easily prepared in large numbers and readily home to secondary lymphoid organs, the primary site of induction of cytotoxic T lymphocyte (CTL) responses. However, most B-cell-based vaccines tested so far failed to induce functional and protective CTLs in in vivo models. Here, we show that B-cells activated through the toll-like receptor-9 (TLR-9) and CD40 up-regulate surface expression of major histocompatibility complex and costimulatory molecules, produce IL-12, and exhibit potent antigen-presenting properties in vitro. Importantly, although administration of peptide-coated or transiently transfected B cells fails to induce immune responses, therapeutic immunization with low numbers of genetically modified B cells stably expressing antigen results in an induction of functional CTLs and protection against the growth of tumor in an animal model. After activation, B cells partially loose their ability to home to organized lymphoid tissue because of the shedding of CD62L; however, this property can be restored by expression of protease-resistant mutant of CD62L. In summary, the data presented in this report suggest that genetically modified activated B cells represent a promising candidate for a cancer vaccine eliciting functional systemic CTLs.
Guo
S
S
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA.
Xu
J
J
Denning
W
W
Hel
Z
Z
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000954:Antigens, Surface / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D017710:Lymphocyte Transfusion / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013945:Thymoma / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D013953:Thymus Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051217:Toll-Like Receptor 9 / Q000276:immunology; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D019013:CD40 Antigens; D019496:Cancer Vaccines; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D018664:Interleukin-12