Abstract
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.
Highlights
Toll-like receptors (TLR) recognize highly conserved molecular patterns of bacteria, virus, and cells of host origin [1]
Mature antigen presenting cells (APCs) are capable of providing a danger context, allowing the immune system to successfully respond to pathogenic antigens [2]
This ability to alter environment is highly relevant in tumor immunity, since tumors are from the host and it is inherently difficult for the immune system to recognize them as immunogenic
Summary
Toll-like receptors (TLR) recognize highly conserved molecular patterns of bacteria, virus, and cells of host origin [1]. This feature allows TLR-expressing immune cells to respond rapidly to a pathological insult. The danger context elicited by TLR agonists allows an initially nonimmunogenic antigen to become immunogenic. This ability to alter environment is highly relevant in tumor immunity, since tumors are from the host and it is inherently difficult for the immune system to recognize them as immunogenic. Immune cells may have encountered certain TLR ligands associated with tumor development, yet this endogenous stimulus is typically not sufficient to induce spontaneous tumor rejection [3]. Previous reports suggest that quantity of ligand may be an issue, because various endogenous TLR agonists that target TLR3, TLR4 and TLR9, have shown various efficacies in boosting an antitumor response [4,5,6]
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