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Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth

Clémence Hollande 1 Jeremy Boussier 1 James Ziai 2 Tamaki Nozawa 2 Vincent Bondet 1 Wilson Phung 2 Binfeng Lu 3 Darragh Duffy 1, 4 Valérie Paradis 5 Vincent Mallet 6 Gerard Eberl 7 Wendy Sandoval 2 Jill Schartner 2 Stanislas Pol 1, 4 Rosa Barreira da Silva 2 Matthew Albert 2, *
* Corresponding author
1 Immunobiologie des Cellules dendritiques
2 Genentech, Inc. [San Francisco]
3 PITT - University of Pittsburgh
4 CRT - Centre de Recherche Translationnelle - Center for Translational Science
5 Service d’Anatomie Pathologique [CHU Beaujon]
6 Service d'hépatologie médicale [CHU Cochin]
7 Microenvironnement et Immunité - Microenvironment and Immunity
Abstract : Post-translational modification of chemokines mediated by the dipeptidyl peptidase DPP4 (CD26) has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional chemokine CXCL10. By extending those initial findings to pre-clinical models of hepatocellular carcinoma and breast cancer, we discovered a distinct mechanism by which inhibition of DPP4 improves anti-tumor responses. Administration of the DPP4 inhibitor sitagliptin resulted in higher concentrations of the chemokine CCL11 and increased migration of eosinophils into solid tumors. Enhanced tumor control was preserved in mice lacking lymphocytes and was ablated after depletion of eosinophils or treatment with degranulation inhibitors. We further demonstrated that tumor-cell expression of the alarmin IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses and that this mechanism contributed to the efficacy of checkpoint-inhibitor therapy. These findings provide insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immunoregulation are inhibited.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-02063831
Contributor : Marie-Christine Vougny Connect in order to contact the contributor
Submitted on : Monday, March 11, 2019 - 3:04:47 PM
Last modification on : Thursday, December 2, 2021 - 11:12:02 AM

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Clémence Hollande, Jeremy Boussier, James Ziai, Tamaki Nozawa, Vincent Bondet, et al.. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. Nature Immunology, Nature Publishing Group, 2019, 20 (3), pp.257-264. ⟨10.1038/s41590-019-0321-5⟩. ⟨pasteur-02063831⟩

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