title: HDAC inhibition suppresses primary immune responses, enhances secondary immune responses, and abrogates autoimmunity during tumor immunotherapy.
abstract: Histone deacetylase inhibitors (HDACi) can modulate innate antiviral responses and render tumors more susceptible to oncolytic viruses (OVs); however, their effects on adaptive immunity in this context are largely unknown. Our present study reveals an unexpected property of the HDACi MS-275 that enhances viral vector-induced lymphopenia leading to selective depletion of bystander lymphocytes and regulatory T cells while allowing expansion of antigen-specific secondary responses. Coadministration of vaccine plus drug during the boosting phase focuses the immune response on the tumor by suppressing the primary immune response against the vaccine vector and enhancing the secondary response against the tumor antigen. Furthermore, improvement of T cell functionality was evident suggesting that MS-275 can orchestrate a complex array of effects that synergize immunotherapy and viral oncolysis. Surprisingly, while MS-275 dramatically enhanced efficacy, it suppressed autoimmune pathology, profoundly improving the therapeutic index.
authors.affiliation: McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Byram W
authors.initials: BW
authors.lastname: Bridle
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.forename: Chantal G
authors.initials: CG
authors.lastname: Lemay
authors.forename: Jean-Simon
authors.initials: JS
authors.lastname: Diallo
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pol
authors.forename: Andrew
authors.initials: A
authors.lastname: Nguyen
authors.forename: Alfredo
authors.initials: A
authors.lastname: Capretta
authors.forename: Rongqiao
authors.initials: R
authors.lastname: He
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Bramson
authors.forename: John C
authors.initials: JC
authors.lastname: Bell
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D008545:Melanoma / Q000188:drug therapy / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*
chemical_list: D056572:Histone Deacetylase Inhibitors