title: Immunotherapeutic potential of B7-DC (PD-L2) cross-linking antibody in conferring antitumor immunity.
abstract: A naturally occurring human antibody potentiates dendritic cell function on cross-linking B7-DC (PD-L2), supporting robust T-cell responses in vitro. Moreover, treatment of dendritic cells with B7-DC cross-linking antibody resulted in secretion of interleukin-12, suggesting a TH1 polarization of this response. Here we show an in vivo immunotherapeutic effect of this B7-DC cross-linking antibody using a poorly immunogenic B16 melanoma tumor model. Treatment of mice systemically with antibody at the time of tumor cell engraftment prevented tumor growth in a CD4 and CD8 T-cell-dependent manner. The protective effect of B7-DC cross-linking antibody treatment was independent of endogenous antibody responses. Tumor-specific CTL precursors could be isolated from lymph nodes draining the tumor site in animals treated with B7-DC cross-linking antibody, but not from those treated with isotype control antibodies. The elicited antitumor responses in vivo were specific and long-lasting. More strikingly, treatment of mice with B7-DC cross-linking antibody after the tumors were established in the lungs resulted in protection in a CD8-, perforin-, and granzyme B-dependent fashion. Depletion of natural killer cells did not block the effects of treatment with B7-DC cross-linking antibody. Together, these findings demonstrate that cross-linking B7-DC with the human IgM antibody sHIgM12 can induce a protective immune response against a weakly antigenic experimental tumor and therefore has potential as a novel immunotherapeutic approach for treating cancer.
authors.affiliation: Departments of Immunology and Neurology, Mayo Clinic College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Radhakrishnan
authors.forename: Loc Tan
authors.initials: LT
authors.lastname: Nguyen
authors.forename: Bogoljub
authors.initials: B
authors.lastname: Ciric
authors.forename: Dallas
authors.initials: D
authors.lastname: Flies
authors.forename: Virginia P
authors.initials: VP
authors.lastname: Van Keulen
authors.forename: Koji
authors.initials: K
authors.lastname: Tamada
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Larry R
authors.initials: LR
authors.lastname: Pease
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D018122:B7-1 Antigen / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D053804:Granzymes; D007116:Immunization, Passive / Q000379:methods*; D007075:Immunoglobulin M / Q000276:immunology* / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D061027:Programmed Cell Death 1 Ligand 2 Protein; D017452:Receptors, IgG; D012697:Serine Endopeptidases / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; C556977:PDCD1LG2 protein, human; C556978:Pdcd1lg2 protein, mouse; D052899:Pore Forming Cytotoxic Proteins; D061027:Programmed Cell Death 1 Ligand 2 Protein; D017452:Receptors, IgG; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases