Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma

The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by im...

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Autores principales:	James M. Henderson, Michelle S. W. Xiang, Jiali Carrie Huang, Stefanie Wetzel, Linxuan Jiang, Jack H. Lai, Wengen Wu, James G. Kench, William W. Bachovchin, Ben Roediger, Geoffrey W. McCaughan, Hui Emma Zhang, Mark D. Gorrell
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ARI-4175 pan-DPP inhibitor DPP4 HCC caspase-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/04651d7d2ee047aa86a1c58c3e6fff83
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spelling	oai:doaj.org-article:04651d7d2ee047aa86a1c58c3e6fff832021-11-11T15:33:43ZDipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma10.3390/cancers132154952072-6694https://doaj.org/article/04651d7d2ee047aa86a1c58c3e6fff832021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5495https://doaj.org/toc/2072-6694The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation. This study investigated the expression and activity of the DPP4 family during the development of HCC and evaluated the efficacy of ARI-4175 in the treatment of early HCC in mice. This first report on this enzyme family in HCC-bearing mice showed DPP9 upregulation in HCC, whereas intrahepatic DPP8/9 and DPP4 enzyme activity levels decreased with age. We demonstrated that ARI-4175 significantly lowered the total number of macroscopic liver nodules in these mice. In addition, ARI-4175 increased intrahepatic inflammatory cell infiltration, including CD8<sup>+</sup> T cell numbers, into the HCC-bearing livers. Furthermore, ARI-4175 activated a critical component of the inflammasome pathway, caspase-1, in these HCC-bearing livers. This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.James M. HendersonMichelle S. W. XiangJiali Carrie HuangStefanie WetzelLinxuan JiangJack H. LaiWengen WuJames G. KenchWilliam W. BachovchinBen RoedigerGeoffrey W. McCaughanHui Emma ZhangMark D. GorrellMDPI AGarticleARI-4175pan-DPP inhibitorDPP4HCCcaspase-1Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5495, p 5495 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ARI-4175 pan-DPP inhibitor DPP4 HCC caspase-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	ARI-4175 pan-DPP inhibitor DPP4 HCC caspase-1 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 James M. Henderson Michelle S. W. Xiang Jiali Carrie Huang Stefanie Wetzel Linxuan Jiang Jack H. Lai Wengen Wu James G. Kench William W. Bachovchin Ben Roediger Geoffrey W. McCaughan Hui Emma Zhang Mark D. Gorrell Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma
description	The mRNA expression of the dipeptidyl peptidase 4 (DPP4) gene family is highly upregulated in human hepatocellular carcinoma (HCC) and is associated with poor survival in HCC patients. Compounds that inhibit the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms that are believed to include NLRP1 activation. This study investigated the expression and activity of the DPP4 family during the development of HCC and evaluated the efficacy of ARI-4175 in the treatment of early HCC in mice. This first report on this enzyme family in HCC-bearing mice showed DPP9 upregulation in HCC, whereas intrahepatic DPP8/9 and DPP4 enzyme activity levels decreased with age. We demonstrated that ARI-4175 significantly lowered the total number of macroscopic liver nodules in these mice. In addition, ARI-4175 increased intrahepatic inflammatory cell infiltration, including CD8<sup>+</sup> T cell numbers, into the HCC-bearing livers. Furthermore, ARI-4175 activated a critical component of the inflammasome pathway, caspase-1, in these HCC-bearing livers. This is the first evidence of caspase-1 activation by a pan-DPP inhibitor in the liver. Our data suggest that targeting the DPP4 enzyme family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.
format	article
author	James M. Henderson Michelle S. W. Xiang Jiali Carrie Huang Stefanie Wetzel Linxuan Jiang Jack H. Lai Wengen Wu James G. Kench William W. Bachovchin Ben Roediger Geoffrey W. McCaughan Hui Emma Zhang Mark D. Gorrell
author_facet	James M. Henderson Michelle S. W. Xiang Jiali Carrie Huang Stefanie Wetzel Linxuan Jiang Jack H. Lai Wengen Wu James G. Kench William W. Bachovchin Ben Roediger Geoffrey W. McCaughan Hui Emma Zhang Mark D. Gorrell
author_sort	James M. Henderson
title	Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma
title_short	Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma
title_full	Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma
title_fullStr	Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma
title_full_unstemmed	Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma
title_sort	dipeptidyl peptidase inhibition enhances cd8 t cell recruitment and activates intrahepatic inflammasome in a murine model of hepatocellular carcinoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/04651d7d2ee047aa86a1c58c3e6fff83
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Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma

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