title: Listeria monocytogenes-derived listeriolysin O has pathogen-associated molecular pattern-like properties independent of its hemolytic ability.
abstract: There is a constant need for improved adjuvants to augment the induction of immune responses against tumor-associated antigens (TAA) during immunotherapy. Previous studies have established that listeriolysin O (LLO), a cholesterol-dependent cytolysin derived from Listeria monocytogenes, exhibits multifaceted effects to boost the stimulation of immune responses to a variety of antigens. However, the direct ability of LLO as an adjuvant and whether it acts as a pathogen-associated molecular pattern (PAMP) have not been demonstrated. In this paper, we show that a detoxified, nonhemolytic form of LLO (dtLLO) is an effective adjuvant in tumor immunotherapy and may activate innate and cellular immune responses by acting as a PAMP. Our investigation of the adjuvant activity demonstrates that dtLLO, either fused to or administered as a mixture with a human papillomavirus type 16 (HPV-16) E7 recombinant protein, can augment antitumor immune responses and facilitate tumor eradication. Further mechanistic studies using bone marrow-derived dendritic cells suggest that dtLLO acts as a PAMP by stimulating production of proinflammatory cytokines and inducing maturation of antigen-presenting cells (APC). We propose that dtLLO is an effective adjuvant for tumor immunotherapy, and likely for other therapeutic settings.
authors.affiliation: Advaxis Inc., Princeton, NJ, USA.
authors.forename: Anu
authors.initials: A
authors.lastname: Wallecha
authors.forename: Laurence
authors.initials: L
authors.lastname: Wood
authors.forename: Zhen-Kun
authors.initials: ZK
authors.lastname: Pan
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Maciag
authors.forename: Vafa
authors.initials: V
authors.lastname: Shahabi
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Paterson
mesh_terms: D000276:Adjuvants, Immunologic / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D001427:Bacterial Toxins / Q000302:isolation & purification / Q000494:pharmacology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006360:Heat-Shock Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D006460:Hemolysin Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods*; D008089:Listeria monocytogenes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D050725:Papillomavirus E7 Proteins / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D019496:Cancer Vaccines; D016207:Cytokines; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; C038705:hlyA protein, Listeria monocytogenes