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Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth.
Nat Immunol 2019; 20(3):257-264NI

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.

Authors+Show Affiliations

Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France. Inserm U1223, Institut Pasteur, Paris, France. École Doctorale Physiologie, Physiopathologie et Thérapeutique, Université Pierre et Marie Curie, Paris, France.Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France. Inserm U1223, Institut Pasteur, Paris, France.Department of Research Pathology, Genentech, South San Francisco, CA, USA.Department of Translational Oncology, Genentech, South San Francisco, CA, USA.Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France. Inserm U1223, Institut Pasteur, Paris, France.Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France. Inserm U1223, Institut Pasteur, Paris, France. Center for Translational Research, Inserm UMS20, Institut Pasteur, Paris, France.Department of Pathology, Physiology and Imaging, Hôpital Beaujon, Clichy, France.Département d'Hépatologie, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes, Paris, France.Microenvironment & Immunity Unit, Inserm U1224, Institut Pasteur, Paris, France.Department of Microchemistry, Proteomics and Lipidomics, Genentech, South San Francisco, CA, USA.Department of Translational Oncology, Genentech, South San Francisco, CA, USA.Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France. Inserm U1223, Institut Pasteur, Paris, France. Center for Translational Research, Inserm UMS20, Institut Pasteur, Paris, France. Département d'Hépatologie, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Université Paris Descartes, Paris, France.Department of Cancer Immunology, Genentech, South San Francisco, CA, USA.Department of Cancer Immunology, Genentech, South San Francisco, CA, USA. albertm7@gene.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30778250

Citation

Hollande, Clémence, et al. "Inhibition of the Dipeptidyl Peptidase DPP4 (CD26) Reveals IL-33-dependent Eosinophil-mediated Control of Tumor Growth." Nature Immunology, vol. 20, no. 3, 2019, pp. 257-264.
Hollande C, Boussier J, Ziai J, et al. Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. Nat Immunol. 2019;20(3):257-264.
Hollande, C., Boussier, J., Ziai, J., Nozawa, T., Bondet, V., Phung, W., ... Albert, M. L. (2019). Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. Nature Immunology, 20(3), pp. 257-264. doi:10.1038/s41590-019-0321-5.
Hollande C, et al. Inhibition of the Dipeptidyl Peptidase DPP4 (CD26) Reveals IL-33-dependent Eosinophil-mediated Control of Tumor Growth. Nat Immunol. 2019;20(3):257-264. PubMed PMID: 30778250.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of the dipeptidyl peptidase DPP4 (CD26) reveals IL-33-dependent eosinophil-mediated control of tumor growth. AU - Hollande,Clémence, AU - Boussier,Jeremy, AU - Ziai,James, AU - Nozawa,Tamaki, AU - Bondet,Vincent, AU - Phung,Wilson, AU - Lu,Binfeng, AU - Duffy,Darragh, AU - Paradis,Valerie, AU - Mallet,Vincent, AU - Eberl,Gérard, AU - Sandoval,Wendy, AU - Schartner,Jill M, AU - Pol,Stanislas, AU - Barreira da Silva,Rosa, AU - Albert,Matthew L, Y1 - 2019/02/18/ PY - 2018/03/21/received PY - 2019/01/14/accepted PY - 2019/2/20/entrez PY - 2019/2/20/pubmed PY - 2019/5/2/medline SP - 257 EP - 264 JF - Nature immunology JO - Nat. Immunol. VL - 20 IS - 3 N2 - 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. SN - 1529-2916 UR - https://www.unboundmedicine.com/medline/citation/30778250/Inhibition_of_the_dipeptidyl_peptidase_DPP4_(CD26)_reveals_IL-33-dependent_eosinophil-mediated_control_of_tumor_growth L2 - http://dx.doi.org/10.1038/s41590-019-0321-5 DB - PRIME DP - Unbound Medicine ER -