Toll-like receptor (TLR) mediated recognition of pathogen associated molecular patterns allows the immune system to rapidly respond to a pathogenic insult. This feature makes TLR agonists attractive agents that can stimulate a favorable immune response. CBLB502 is a pharmacologically optimized TLR5 agonist derived from Salmonella enterica flagellin. In this study, we examined the effect of CBLB502 on tumor immunity using two lymphoma models, both of which do not express TLR5, and thus do not directly respond to CBLB502. Upon challenge with the T cell lymphoma RMAS, CBLB502 treatment after tumor inoculation protects approximately 50% of C57BL/6 mice from death caused by tumor growth. This protective effect is both natural killer (NK) cell and perforin dependent. In addition, CBLB502 stimulates clearance of the B cell lymphoma A20 in BALB/c mice in a CD8+ T cell dependent fashion. ImageStream flow cytometry analyses reveal that CD11b+ and CD11c+ cells, but neither NK nor T cells, directly respond to CBLB502 as determined by nuclear translocation of NFκB. NFκB can regulate a variety of pro-inflammatory cytokines; accordingly, CBLB502 increases serum levels of IL-6, IL-15, TNFα, and IFN-γ. Furthermore, CBLB502 promotes antigen-presenting cell maturation as evidenced by CD86 upregulation. These findings demonstrate that CBLB502 can stimulate a robust antitumor immune response by indirectly activating cytotoxic lymphocytes through TLR5-expressing accessory immune cells.
- Copyright © 2013 by The American Association of Immunologists, Inc.