Val-boroPro accelerates T cell priming via modulation of dendritic cell trafficking resulting in complete regression of established murine tumors
| Autor: | Terry J. Fry, Meghaan P. Walsh, Martin Guimond, Jessica P. E. Davis, Shannon M. Larabee, Yongzhi Cui, William W. Bachovchin, Brynn B. Duncan, Su Young Kim, Aviva C. Krauss |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Male Adoptive cell transfer Mouse medicine.medical_treatment T-Lymphocytes Priming (immunology) lcsh:Medicine CD8-Positive T-Lymphocytes Immunotherapy Adoptive Mice Neoplasms Interferon gamma lcsh:Science Vaccines Multidisciplinary biology Vaccination Remission Induction Animal Models Dipeptides Boronic Acids medicine.anatomical_structure Oncology Medicine Cytokines Female Immunotherapy Antibody Chemokines Cancer Prevention medicine.drug Research Article T cell Immune Cells Immunology Antigen-Presenting Cells Cancer Vaccines Immune system Model Organisms Adjuvants Immunologic Cell Line Tumor Vaccine Development medicine Animals Biology lcsh:R Immunity Dendritic cell Dendritic Cells Disease Models Animal Cancer research biology.protein Clinical Immunology lcsh:Q Lymph Nodes |
| Zdroj: | PLoS ONE, Vol 8, Iss 3, p e58860 (2013) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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