Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation.
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.
French
Ruth R
RR
Cancer Sciences Division, School of Medicine, Tenovus Research Laboratory, University of Southampton, Tremona Road, Southampton, UK.
Taraban
Vadim Y
VY
Crowther
Graham R
GR
Rowley
Tania F
TF
Gray
Juliet C
JC
Johnson
Peter W
PW
Tutt
Alison L
AL
Al-Shamkhani
Aymen
A
Glennie
Martin J
MJ
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
D000911:Antibodies, Monoclonal; D053282:CD27 Ligand; D019013:CD40 Antigens; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha