title: Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors.
abstract: Although tumors naturally prime adaptive immune responses, tolerance may limit the capacity to control progression and can compromise effectiveness of immune-based therapies for cancer. Post-proline cleaving enzymes (PPCE) modulate protein function through N-terminal dipeptide cleavage and inhibition of these enzymes has been shown to have anti-tumor activity. We investigated the mechanism by which Val-boroPro, a boronic dipeptide that inhibits post-proline cleaving enzymes, mediates tumor regression and tested whether this agent could serve as a novel immune adjuvant to dendritic cell vaccines in two different murine syngeneic murine tumors. In mice challenged with MB49, which expresses the HY antigen complex, T cell responses primed by the tumor with and without Val-boroPro were measured using interferon gamma ELISPOT. Antibody depletion and gene-deficient mice were used to establish the immune cell subsets required for tumor regression. We demonstrate that Val-boroPro mediates tumor eradication by accelerating the expansion of tumor-specific T cells. Interestingly, T cells primed by tumor during Val-boroPro treatment demonstrate increased capacity to reject tumors following adoptive transfer without further treatment of the recipient. Val-boroPro -mediated tumor regression requires dendritic cells and is associated with enhanced trafficking of dendritic cells to tumor draining lymph nodes. Finally, dendritic cell vaccination combined with Val-boroPro treatment results in complete regression of established tumors. Our findings demonstrate that Val-boroPro has antitumor activity and a novel mechanism of action that involves more robust DC trafficking with earlier priming of T cells. Finally, we show that Val-boroPro has potent adjuvant properties resulting in an effective therapeutic vaccine.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Meghaan P
authors.initials: MP
authors.lastname: Walsh
authors.forename: Brynn
authors.initials: B
authors.lastname: Duncan
authors.forename: Shannon
authors.initials: S
authors.lastname: Larabee
authors.forename: Aviva
authors.initials: A
authors.lastname: Krauss
authors.forename: Jessica P E
authors.initials: JP
authors.lastname: Davis
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Cui
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
authors.forename: William
authors.initials: W
authors.lastname: Bachovchin
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D001897:Boronic Acids / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D004151:Dipeptides / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D016219:Immunotherapy, Adoptive; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D012074:Remission Induction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D001897:Boronic Acids; D019496:Cancer Vaccines; D018925:Chemokines; D016207:Cytokines; D004151:Dipeptides; C477478:PT-100 dipeptide
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