A flagellin-derived toll-like receptor 5 agonist stimulates cytotoxic lymphocyte-mediated tumor immunity.
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.
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Nicholas D
ND
Leigh
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Guanglin
G
Bian
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Xilai
X
Ding
Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Hong
H
Liu
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Semra
S
Aygun-Sunar
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Lyudmila G
LG
Burdelya
Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Andrei V
AV
Gudkov
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
Xuefang
X
Cao
D056704:Adaptive Immunity / Q000187:drug effects; D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000097:blood; D005408:Flagellin / Q000737:chemistry*; D007113:Immunity, Innate / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054353:Perforin / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000819:agonists*; D015854:Up-Regulation / Q000187:drug effects
D000276:Adjuvants, Immunologic; C528306:CBLB502; D016207:Cytokines; D010455:Peptides; D051198:Toll-Like Receptor 5; D054353:Perforin; D005408:Flagellin