Article | Published:

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

Nature Immunology volume 16, pages 850858 (2015) | Download Citation

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.

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Acknowledgements

We thank S. Amigorena, P. Bousso, S. Turley and D. DiGregorio for critical reading of the manuscript. We also thank G. Hangoc (Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA) for providing the Dpp4−/− mice and C. Reis e Sousa (Immunobiology Laboratory, The Francis Crick Institute, London, UK) for the B16F10-OVA tumor cells. We thank M.A. Nicola (Plateforme d'imagerie dynamique, Institut Pasteur, Paris, France) for providing FVB CAG-luciferase transgenic mice. We acknowledge C. Hollande, D. Duffy, A. Casrouge, V. Bondet, V. Mallet, M. Buckwalter, T. Canton, M.A. Nicola and F. Cretien for advice and support. Funding was provided by the Institut Pasteur (Pasteur-Roux post-doctoral fellowship to R.B.d.S.), the Pasteur Foundation (fellowship to M.E.L.), the Ligue Contre le Cancer (M.L.A.), the Fondation ARC pour la recherche sur le cancer (M.L.A.) and the French government's Invest in the Future Program, managed by the Agence Nationale de la Recherche (LabEx Immuno-Onco (R.B.d.S., M.E.L., N.Y., M.A.I. and M.L.A.)).

Author information

Affiliations

  1. Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France.

    • Rosa Barreira da Silva
    • , Melissa E Laird
    • , Nader Yatim
    • , Molly A Ingersoll
    •  & Matthew L Albert
  2. Inserm U818, Paris, France.

    • Rosa Barreira da Silva
    • , Melissa E Laird
    • , Nader Yatim
    • , Molly A Ingersoll
    •  & Matthew L Albert
  3. Human Histopathology and Animal Models, Institut Pasteur, Paris, France.

    • Laurence Fiette
  4. Université Paris Descartes–Sorbonne Paris Cité, Paris, France.

    • Laurence Fiette

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Contributions

R.B.d.S. and M.L.A. designed the study. R.B.d.S. and M.E.L. designed, carried out and analyzed experiments. L.F. conducted histological experiments. N.Y. and M.A.I. provided technical and intellectual assistance. R.B.d.S. and M.L.A. wrote the manuscript. M.L.A. supervised the study.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Matthew L Albert.

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DOI

https://doi.org/10.1038/ni.3201

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