Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors

• Published in: PloS one Vol. 8; no. 3; p. e58860
• Main Authors: Walsh, Meghaan P, Duncan, Brynn, Larabee, Shannon, Krauss, Aviva, Davis, Jessica P E, Cui, Yongzhi, Kim, Su Young, Guimond, Martin, Bachovchin, William, Fry, Terry J
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12.03.2013; Public Library of Science (PLoS)
• Subjects: Adaptive control; Adaptive immunity; Adjuvants, Immunologic; Adoptive transfer; Animals; Antibodies; Anticancer properties; Antigens; Antitumor activity; Antitumor agents; Biology; Bone marrow; Boronic Acids - immunology; Cancer; Cancer therapies; Cancer treatment; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Chemokines; Chemokines - immunology; Cytokines - immunology; Cytokines - metabolism; Dendritic cells; Dendritic Cells - immunology; Dipeptides - immunology; Disease Models, Animal; Disease susceptibility; Enzyme-linked immunosorbent assay; Enzymes; Female; Fibroblasts; Health aspects; House mouse; HY antigen; Immune response; Immunological tolerance; Immunotherapy; Immunotherapy, Adoptive; Interferon; Lymph nodes; Lymph Nodes - immunology; Lymphatic system; Lymphocytes; Lymphocytes T; Male; Medical research; Medicine; Mice; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Oncology; Pediatrics; Priming; Proline; Proteins; Regression; Remission Induction; Rodents; T cells; T-Lymphocytes - immunology; Transgenic animals; Tumors; Vaccination; Vaccines; United States > US; Maryland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0058860

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.