Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy.

Abstract	The success of antitumor immune responses depends on the infiltration of solid tumors by effector T cells, a process guided by chemokines. Here we show that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors. Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10 and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade. These findings provide direct in vivo evidence for control of lymphocyte trafficking via CXCL10 cleavage and support the use of DPP4 inhibitors for stabilizing biologically active forms of chemokines as a strategy to enhance tumor immunotherapy.
Authors	Rosa Barreira da Silva, Melissa E Laird, Nader Yatim, Laurence Fiette, Molly A Ingersoll, Matthew L Albert
Journal	Nature immunology (Nat Immunol) Vol. 16 Issue 8 Pg. 850-8 (Aug 2015) ISSN: 1529-2916 [Electronic] United States
PMID	26075911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Chemokine CXCL10 Chemokines Cxcr3 protein, mouse Dipeptidyl-Peptidase IV Inhibitors Pyrazines Receptors, CXCR3 Triazoles Dipeptidyl Peptidase 4 Dpp4 protein, mouse Sitagliptin Phosphate
Topics	Adoptive Transfer Animals Cell Line, Tumor Cell Movement (drug effects, immunology) Chemokine CXCL10 (immunology, metabolism) Chemokines (immunology, metabolism) Dipeptidyl Peptidase 4 (genetics, immunology, metabolism) Dipeptidyl-Peptidase IV Inhibitors (pharmacology) Female Flow Cytometry Immunotherapy (methods) Lymphocytes (immunology, metabolism) Male Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Neoplasms, Experimental (genetics, immunology, therapy) Pyrazines (pharmacology) Receptors, CXCR3 (immunology, metabolism) Sitagliptin Phosphate Triazoles (pharmacology)

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