title: IL-6-inducing whole yeast-based immunotherapy directly controls IL-12-dependent CD8 T-cell responses.
abstract: In current clinical trails, whole yeast-based immunotherapy expressing hepatitis C viral antigens demonstrated statistically significant improvement in end of treatment responses when combined with type I interferon based standard of care, even in standard of care resistant patients. Although preclinical data suggest yeast vaccination, such as type I interferon, facilitates CD8 T-cell immunity, the capacity of yeast to generate immunity in patients resistant to type I interferon calls into question the mechanism(s) underpinning the efficacy of this approach. We show yeast and a Toll-like receptor exclusive agonist, Pam3Cys, differ in CD8 T-cell generation when combined with an agonistic CD40 antibody. Although both yeast and PamCys were largely Toll-like receptor dependent, the primary CD8 response generated by yeast was significantly less than Pam3Cys in wild-type hosts even in a CD4 T-cell-deficient setting. In addition, immunization of IL6 mice with yeast produced a 3-fold to 6-fold increased CD8 response while the Pam3Cys response was unaffected. The yeast but not Pam3Cys-driven CD8 response was inhibited in both wild-type and IL-6 hosts by blocking interleukin (IL)-12. In addition, IL6 mice had increased CD86 expression on their dendritic cells after yeast immunization also inhibited by IL-12 blockade. Collectively, our results indicate the CD8 T-cell response to yeast but not Pam3Cys is influenced by IL-6-mediated control of IL-12 critical for dendritic cell activation. To our knowledge this is the first demonstration that yeast directly influence IL-12-associated CD8 T-cell immunity providing an additional route whereby recombinant yeast may provide efficacy independent of type I interferon.
authors: Integrated Department of Immunology, School of Medicine, University of Colorado Denver, Aurora, CO, USA.
authors: Beth A
authors: BA
authors: Tamburini
authors: Ross M
authors: RM
authors: Kedl
authors: Donald
authors: D
authors: Bellgrau
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003545:Cysteine / Q000008:administration & dosage / Q000031:analogs & derivatives; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007167:Immunotherapy / Q000379:methods*; D007370:Interferon Type I / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008074:Lipoproteins / Q000008:administration & dosage; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012441:Saccharomyces cerevisiae / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D014611:Vaccination
chemical_list: D019013:CD40 Antigens; D007370:Interferon Type I; D015850:Interleukin-6; D008074:Lipoproteins; D018664:Interleukin-12; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D003545:Cysteine