A flagellin-derived toll-like receptor 5 agonist stimulates cytotoxic lymphocyte-mediated tumor immunity

Research output: Contribution to journalArticle

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.

Details

Authors
  • Nicholas D Leigh
  • Guanglin Bian
  • Xilai Ding
  • Hong Liu
  • Semra Aygun-Sunar
  • Lyudmila G Burdelya
  • Andrei V Gudkov
  • Xuefang Cao
External organisations
  • Roswell Park Cancer Institute
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area
  • Cancer and Oncology

Keywords

  • Adaptive Immunity/drug effects, Adjuvants, Immunologic/chemistry, Animals, Cell Line, Tumor, Cytokines/blood, Flagellin/chemistry, Immunity, Innate/drug effects, Lymphocytes/drug effects, Lymphoma, T-Cell/blood, Mice, Peptides/chemistry, Perforin/metabolism, Toll-Like Receptor 5/agonists, Up-Regulation/drug effects
Original languageEnglish
Article numbere85587
JournalPLoS ONE
Volume9
Issue number1
Publication statusPublished - 2014 Jan 14
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes

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