CD26 enzymatic activity modulates efficient migration of adoptively transferred cancer-specific T cells to solid tumors

Abstract The restricted ability of adoptively transferred T cells to eradicate solid tumors limits their use in some patients. Efforts to improve ACT for solid tumors aim to identify strategies that poise T cells for migration. 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 tumors. We therefore sought to investigate the functional importance of CD26 on T cells destined for ACT. We transferred tumor specific CD26+ T cells into melanoma-bearing CD26−/− mice and blocked the CD26 enzymatic activity of the donor cells in vivo with sitagliptin, an established competitive inhibitor of CD26. Sitagliptin-treated mice eventually succumbed to tumor burden, while tumors in untreated mice were ablated, eliciting long-term cures exceeding 4 months. Additional analysis determined that tumor infiltrating donor and host T cells diminished with sitagliptin treatment. A 32-plex cytokine array of peripheral blood plasma from these mice revealed a global diminishment of cytokines and chemokines, signifying that the inflammatory response of the T cells was dampened with sitagliptin treatment. Further experiments examined how CD26+ T cells responded to tumor trafficking signals using 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 mount a functional response to tumor antigen. These data reveal that the enzymatic activity of CD26 is important for the ability of T cells to migrate to malignant sites and supports an effective antitumor response.