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Role of dipeptidyl peptidase-4 in the regulation of leucocyte trafficking in hepatocellular carcinoma

Abstract : Dipeptidyl peptidase-4 (DPP4 or CD26)–mediated post-translational modification of chemokines has been shown to negatively regulate lymphocyte trafficking, and its inhibition enhances T cell migration and tumor immunity by preserving functional CXCL10. In extending these initial findings to humans and pre-clinical hepatocellular carcinoma models, we discovered a new mechanism whereby DPP4 inhibition improves anti-tumor responses by eosinophil recruitment. Specifically, administration of DPP4 inhibitors (DPP4i) resulted in higher concentrations of CCL11 (or eotaxin) and increased CCR3-mediated eosinophil migration into mouse tumors. Enhanced tumor control was observed upon treatment with DPP4i, an effect strikingly preserved in Rag2–/– mice, and abrogated only upon depletion of eosinophils or inhibition of their degranulation. We further demonstrated that tumor expression of IL-33 was necessary and sufficient for eosinophil-mediated anti-tumor responses, and that this mechanism contributed to checkpoint inhibitor efficacy. These findings provide new insight into IL-33- and eosinophil-mediated tumor control, revealed when endogenous mechanisms of DPP4 immune regulation are inhibited.
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Submitted on : Monday, October 1, 2018 - 1:06:34 AM
Last modification on : Friday, October 23, 2020 - 4:37:53 PM
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  • HAL Id : tel-01884413, version 1


Clémence Hollande. Role of dipeptidyl peptidase-4 in the regulation of leucocyte trafficking in hepatocellular carcinoma. Immunology. Université Pierre et Marie Curie - Paris VI, 2017. English. ⟨NNT : 2017PA066446⟩. ⟨tel-01884413⟩



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