513 CD26 enzymatic activity modulates efficient migration of adoptively transferred T cells to solid tumors

BackgroundThe inadequate ability of adoptively transferred T cells to eradicate solid tumors limits their use in treatments for patients afflicted with those cancers. Efforts to improve ACT for solid tumors aim to identify strategies that poise T cells for optimal response. We have previously identified a specific subset of CD4 T cells which express high levels of the ubiquitous ectoenzyme dipeptidyl peptidase-4 (DPP-4), also known as CD26, that produce a tremendous antitumor response in solid tumor models. We therefore sought to investigate the importance of CD26 on T cells destined for ACT.MethodsWe adoptively transferred tumor specific CD26+ T cells into melanoma tumor-bearing CD26-/- mice, and continuously blocked the CD26 enzymatic activity of the donor cells in vivo with sitagliptin, an established competitive inhibitor of CD26.ResultsTumors in sitagliptin-treated mice eventually reached study endpoint, while tumors untreated mice were regressed for 130+ days. Tumor infiltration of donor cells and host CD8 and CD4 cells was diminished with sitagliptin treatment. A 32-plex cytokine array of blood plasma revealed a diminished profile of cytokines and chemokines, indicating that the inflammatory response of the T cells was dampened with sitagliptin treatment. Further experiments characterized the ability of CD26+ T cells to respond to tumor trafficking signals with a transwell migration assay and found that sitagliptin treatment significantly impaired their migratory capacity. However, sitagliptin did not impair the ability of T cells to functionally respond to antigen.ConclusionsThese data suggest that the enzymatic activity of CD26 is important for the ability of T cells to migrate to the tumor site in order to mount an effective antitumor response. Further investigations into the mechanism behind the role of CD26 are ongoing.Ethics ApprovalThis study was approved by the Medical University of South Carolina’s IACUC, protocol #00488