title: 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.affiliation: 1] Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France. [2] Inserm U818, Paris, France.
authors.forename: Rosa
authors.initials: R
authors.lastname: Barreira da Silva
authors.affiliation: 1] Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France. [2] Inserm U818, Paris, France.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Laird
authors.affiliation: 1] Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France. [2] Inserm U818, Paris, France.
authors.forename: Nader
authors.initials: N
authors.lastname: Yatim
authors.affiliation: 1] Human Histopathology and Animal Models, Institut Pasteur, Paris, France. [2] Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Fiette
authors.affiliation: 1] Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France. [2] Inserm U818, Paris, France.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Ingersoll
authors.affiliation: 1] Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France. [2] Inserm U818, Paris, France.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D007167:Immunotherapy / Q000379:methods*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D011719:Pyrazines / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology
chemical_list: D054357:Chemokine CXCL10; D018925:Chemokines; C515188:Cxcr3 protein, mouse; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D054367:Receptors, CXCR3; D014230:Triazoles; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000068900:Sitagliptin Phosphate