title: Modulating the innate immune activity in murine tumor microenvironment by a combination of inducer molecules attached to microparticles.
abstract: Targeted cancer immunotherapy is challenging due to the cellular diversity and imposed immune tolerance in the tumor microenvironment (TME). A promising route to overcome those drawbacks may be by activating innate immune cells (IIC) in the TME, toward tumor destruction. Studies have shown the ability to "re-educate" pro-tumor-activated IIC toward antitumor responses. The current research aims to stimulate such activation using a combination of innate activators loaded onto microparticles (MP). Four inducers of Toll-like receptors 4 and 7, complement C5a receptor (C5aR) and gamma Fc receptor and their combinations were loaded on MP, and their influence on immune cell activation evaluated. MP stimulation of immune cell activation was tested in vitro and in vivo using a subcutaneous B16-F10 melanoma model induced in C57BL6 mice. Exposure to the TLR4 ligand lipopolysaccharide (LPS) bound to MP-induced acute inflammatory cytokine and chemokine activity in vitro and in vivo, with the elevation of CD45(+) leukocytes in particular GR-1(+) neutrophils and F4/80 macrophages in the TME. Nevertheless, LPS alone on MP was insufficient to significantly delay tumor progression. LPS combined with the C5aR ligand C5a-pep on the same MP resulted in a similar inflammation activation pattern. However, interleukin-10 levels were lower, and tumor growth was significantly delayed. Mixtures of these two ligands on separate MP did not yield the same cytokine activation pattern, demonstrating the importance of the cells' dual activation. The results suggest that combining inducers of distinct innate immune activation pathways holds promise for successful redirection of TME-residing IIC toward anti-tumoral activation.
authors.affiliation: MIGAL - Galilee Research Institute, P.O. Box 831, 11016, Kiryat Shmona, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Shahar
authors.forename: Raphael
authors.initials: R
authors.lastname: Gorodetsky
authors.forename: Elina
authors.initials: E
authors.lastname: Aizenshtein
authors.forename: Lior
authors.initials: L
authors.lastname: Lalush
authors.forename: Jacob
authors.initials: J
authors.lastname: Pitcovski
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000276:immunology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D059016:Tumor Microenvironment / Q000187:drug effects* / Q000276:immunology*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides