title: Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+ T-cell axis.
abstract: Activation of an anticancer innate immune response is highly desirable because of its inherent ability to generate an adaptive antitumor T-cell response. However, insufficient safety of innate immune modulators limits clinical use to topical applications. Toll-like receptor 5 (TLR5) agonists are favorably positioned as potential systemic immunotherapeutic agents because of unusual tissue specificity of expression, uniquely safe profile of induced cytokines, and antitumor efficacy demonstrated in a number of animal models. Here, we decipher the molecular and cellular events underlying the metastasis suppressive activity of entolimod, a clinical stage TLR5 agonist that activates NF-κB-, AP-1-, and STAT3-driven immunomodulatory signaling pathways specifically within the liver. Used as a single agent in murine colon and mammary metastatic cancer models, entolimod rapidly induces CXCL9 and -10 that support homing of blood-borne CXCR3-expressing NK cells to the liver predominantly through an IFN-γ signaling independent mechanism. NK cell-dependent activation of dendritic cells is followed by stimulation of a CD8(+) T-cell response, which exert both antimetastatic effect of entolimod and establishment of tumor-specific and durable immune memory. These results define systemically administered TLR5 agonists as organ-specific immunoadjuvants, enabling efficient antitumor vaccination that does not depend on identification of tumor-specific antigens.
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Craig M
authors.initials: CM
authors.lastname: Brackett
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Bojidar
authors.initials: B
authors.lastname: Kojouharov
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Jean
authors.initials: J
authors.lastname: Veith
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Kellee F
authors.initials: KF
authors.lastname: Greene
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Lyudmila G
authors.initials: LG
authors.lastname: Burdelya
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263;
authors.forename: Sandra O
authors.initials: SO
authors.lastname: Gollnick
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263; scott.abrams@roswellpark.org andrei.gudkov@roswellpark.org.
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.affiliation: Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263; Cleveland BioLabs, Inc., Buffalo, NY 14203 scott.abrams@roswellpark.org andrei.gudkov@roswellpark.org.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D010455:Peptides / Q000494:pharmacology*; D051198:Toll-Like Receptor 5 / Q000819:agonists*
chemical_list: C528306:CBLB502; D010455:Peptides; D051198:Toll-Like Receptor 5
keywords: breast cancer; cancer immunotherapy; colorectal cancer; innate immunity; liver
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