title: Perioperative treatment with the new synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects.
abstract: The use of TLR agonists as an anti-cancer treatment is gaining momentum given their capacity to activate various host cellular responses through the secretion of inflammatory cytokines and type-I interferons. It is now also recognized that the perioperative period is a window of opportunity for various interventions aiming at reducing the risk of cancer metastases-the major cause of cancer related death. However, immune-stimulatory approach has not been used perioperatively given several contraindications to surgery. To overcome these obstacles, in this study, we used the newly introduced, fully synthetic TLR-4 agonist, Glucopyranosyl Lipid-A (GLA-SE), in various models of cancer metastases, and in the context of acute stress or surgery. Without exerting evident adverse effects, a single systemic administration of GLA-SE rapidly and dose dependently elevated both innate and adaptive immunity in the circulation, lungs and the lymphatic system. Importantly, GLA-SE treatment led to reduced metastatic development of a mammary adenocarcinoma and a colon carcinoma by approximately 40-75% in F344 rats and BALB/c mice, respectively, at least partly through elevating marginating-pulmonary NK cell cytotoxicity. GLA-SE is safe and well tolerated in humans, and currently is used as an adjuvant in phase-II clinical trials. Given that the TLR-4 receptor and its signaling cascade is highly conserved throughout evolution, our current results suggest that GLA-SE may be a promising immune stimulatory agent in the context of oncological surgeries, aiming to reduce long-term cancer recurrence.
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Pini
authors.initials: P
authors.lastname: Matzner
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Sorski
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Lee
authors.initials: L
authors.lastname: Shaashua
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Ely
authors.initials: E
authors.lastname: Elbaz
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Hagar
authors.initials: H
authors.lastname: Lavon
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Rivka
authors.initials: R
authors.lastname: Melamed
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Ella
authors.initials: E
authors.lastname: Rosenne
authors.affiliation: Department of Psychology, University of California, Berkely, California.
authors.forename: Neta
authors.initials: N
authors.lastname: Gotlieb
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Benbenishty
authors.affiliation: Infectious Disease Research Institute (IDRI), Seattle, Washington.
authors.forename: Steve G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Neuro-Immunology Research Unit, School of Psychological Sciences Tel-Aviv University, Tel Aviv-Yafo, Israel.|Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv-Yafo, Israel.
authors.forename: Shamgar
authors.initials: S
authors.lastname: Ben-Eliyahu
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D005960:Glucosides / Q000494:pharmacology*; D008050:Lipid A / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009374:Neoplasms, Experimental / Q000473:pathology*; D059035:Perioperative Period; D051381:Rats; D011916:Rats, Inbred F344; D051197:Toll-Like Receptor 4 / Q000819:agonists*
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D005960:Glucosides; D008050:Lipid A; D051197:Toll-Like Receptor 4; C000608161:glucopyranosyl lipid-A
keywords: CT26; GLA; MADB106; NK; TLR-4; in vivo; metastases; perioperative; stress; surgery