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.
Highlights
Multiple lines of evidence have conclusively demonstrated that natural immunity can contribute to control of tumor growth [1,2]
Antitumor activity was observed with 5 days of Val-boroPro treatment following the orthotopic implantation of cells from non tumor-bearing donors; closed triangles, Rag 2/2 mice injected with MB49 but not receiving T cells
FAP may be a sufficient target in some murine tumor models, we demonstrate that extracellular enzyme inhibition is insufficient in our models, suggesting intracellular proteases may be relevant targets for boronated dipeptides with antitumor activity
Summary
Multiple lines of evidence have conclusively demonstrated that natural immunity can contribute to control of tumor growth [1,2]. Once progression occurs, the widely held assumption is that the tumor has evaded the immune response and that the host has become immunologically tolerant [3,4,5,6,7]. This is important in the context of clinically relevant immune-based therapy where most patients present with established tumor.
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