Toll-like receptor (TLR) mediated recognition of
pathogen associated molecular patterns allows the immune system to rapidly respond to a pathogenic insult. The "danger context" elicited by
TLR agonists allows an initially non-immunogenic
antigen to become immunogenic. This ability to alter environment is highly relevant in
tumor immunity, since it is inherently difficult for the immune system to recognize host-derived
tumors as immunogenic. However, immune cells may have encountered certain TLR
ligands associated with
tumor development, yet the endogenous stimulation is typically not sufficient to induce spontaneous
tumor rejection. Of special interest are TLR5 agonists, because there are no endogenous
ligands that bind TLR5.
CBLB502 is a pharmacologically optimized TLR5 agonist derived from Salmonella enterica
flagellin. We examined the effect of
CBLB502 on
tumor immunity using two syngeneic
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 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. Analysis on the cellular level via ImageStream flow cytometry reveals that CD11b(+) and CD11c(+) cells, but neither NK nor T cells, directly respond to
CBLB502 as determined by NFκB nuclear translocation. Our findings demonstrate that
CBLB502 stimulates a robust antitumor response by directly activating TLR5-expressing accessory immune cells, which in turn activate cytotoxic lymphocytes.