title: Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation.
abstract: Growing evidence points to the potential of agonistic anti-CD40 mAbs as adjuvants for vaccination against cancer. These appear to act by maturing dendritic cells (DCs) and allowing them to prime CD8 cytotoxic T lymphocytes (CTLs). Although it is well established that optimal T-cell priming requires costimulation via B7:CD28, recent studies emphasize the contribution of TNF receptors to this process. To understand how anti-CD40 mAbs trigger effective antitumor immunity, we investigated the role of TNFR superfamily members CD27 and 4-1BB in the generation of this immunity and showed that, although partially dependent on 4-1BB:4-1BBL engagement, it is completely reliant on CD27:CD70 interactions. Importantly, blocking CD70, and to some extent 4-1BBL, during anti-CD40 treatment prevented accumulation of tumor-reactive T cells and subsequent tumor protection. However, it did not influence changes in DC number, phenotype, nor the activity of CTLs once immunity was established. We conclude that CD27:CD70 and 4-1BB:4-1BBL interactions are needed for DC-driven accumulation of antitumor CTLs following anti-CD40 mAb treatment. Finally, in support of the critical role for CD70:CD27, we show for the first time that agonistic anti-CD27 mAbs given without a DC maturation signal completely protect tumor-bearing mice and provide a highly potent reagent for boosting antitumor T-cell immunity.
authors.affiliation: Cancer Sciences Division, School of Medicine, Tenovus Research Laboratory, University of Southampton, Tremona Road, Southampton, UK.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: French
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Taraban
authors.forename: Graham R
authors.initials: GR
authors.lastname: Crowther
authors.forename: Tania F
authors.initials: TF
authors.lastname: Rowley
authors.forename: Juliet C
authors.initials: JC
authors.lastname: Gray
authors.forename: Peter W
authors.initials: PW
authors.lastname: Johnson
authors.forename: Alison L
authors.initials: AL
authors.lastname: Tutt
authors.forename: Aymen
authors.initials: A
authors.lastname: Al-Shamkhani
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D053282:CD27 Ligand / Q000096:biosynthesis; D019013:CD40 Antigens / Q000096:biosynthesis*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D007167:Immunotherapy / Q000379:methods*; D008223:Lymphoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry
chemical_list: D000911:Antibodies, Monoclonal; D053282:CD27 Ligand; D019013:CD40 Antigens; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha