title: 1 alpha, 25-dihydroxylvitamin D3 promotes Bacillus Calmette-Guérin immunotherapy of bladder cancer.
abstract: Bacillus Calmette-Guérin (BCG), a vaccine against tuberculosis(TB), has been used and proven to be one of the most effective treatments for non-muscle invasive bladder cancer (BCa). However, the mechanisms of BCG action have not been completely understood, thereby limiting the improvement of BCG therapy. Vitamin D deficiency has been associated with a high risk of TB infection, and the beneficial effect of UV exposure in TB patients was proven to be mediated via activation of vitamin D signals of innate immune cells. Thus, vitamin D signals might be involved in mediating BCG immunotherapy. To test this hypothesis, we examined the impact of 1 alpha, 25-dihydroxyvitamin D3 (1,25-VD) on BCG-induced response in BCa cells and macrophage cells. Our data revealed that 1,25-VD promotes BCG-induced interleukin 8 (IL-8) secretion by BCa cells, consequently inducing the migration of macrophage, THP-1. This THP-1 cell migration promoted by 1,25-VD can be blocked by IL-8 neutralized antibody. Furthermore, 1,25-VD increased BCG-induced expression of macrophage markers in THP-1 cell, and enhanced the BCG-induced THP-1 cytotoxicity against low-grade BCa cells. Importantly, a pre-clinical trial using the N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced BCa mouse model revealed that intravesical co-treatment of 1,25-VD with BCG can prolong mice survival. These data demonstrate a novel mechanism by which 1,25-VD promotes BCG-mediated anti-BCa pathways and provides a platform for improving BCG efficacy with combination of 1,25-VD.
authors.affiliation: Department of Urology, University of Rochester, Rochester, New York, USA.
authors.forename: Jong-Wei
authors.initials: JW
authors.lastname: Hsu
authors.forename: Peng-Nien
authors.initials: PN
authors.lastname: Yin
authors.forename: Ronald
authors.initials: R
authors.lastname: Wood
authors.forename: James
authors.initials: J
authors.lastname: Messing
authors.forename: Edward
authors.initials: E
authors.lastname: Messing
authors.forename: Yi-Fen
authors.initials: YF
authors.lastname: Lee
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001500:BCG Vaccine / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D016209:Interleukin-8; D002117:Calcitriol