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

James M Henderson,Ben Roediger,James G Kench,Wengen Wu,Linxuan Jiang,Stefanie Wetzel,Jiali Carrie Huang,Michelle S W Xiang,Geoffrey W Mccaughan,Hui Emma Zhang,Mark D Gorrell,Jack H Lai,William W Bachovchin

doi:10.3390/cancers13215495

Abstract

Simple SummaryThis study reported, for the first time, on the expression and activity of the dipeptidyl peptidase 4 (DPP4) family during the development of hepatocellular carcinoma (HCC). We also demonstrated that the pan-DPP inhibitory compound ARI-4175 significantly reduced the number of macroscopic liver nodules in a mouse HCC model. ARI-4175 increased intrahepatic inflammatory cell infiltration, CD8+ T cell numbers and caspase-1-mediated inflammasome activation in the HCC-bearing liver. Thus, this study provides promising data on the efficacy of ARI-4175 in the treatment of early-stage HCC. Targeting the DPP4 family may be a novel and effective approach to promote anti-tumour immunity in HCC via caspase-1 activation.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+ 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.

Highlights

Liver cancer is the sixth most common cancer and the fourth most common cause of cancer mortality worldwide [1,2]
We previously reported that intrahepatic Dpp8 and Dpp9 mRNA levels are upregulated in fibrotic mouse livers after 3 weeks of CCl4 treatment [34]
No change in Dpp8 or Dpp9 whole-liver mRNA expression was observed among the control and two treatment groups (DEN/TAA and DEN/TAA/high-fat diet (HFD) groups) at 24 weeks of age (Figure 1A)

Summary

Introduction

Liver cancer is the sixth most common cancer and the fourth most common cause of cancer mortality worldwide [1,2]. 70-85% of primary liver cancer cases [3]. Multikinase inhibitors with anti-proliferative and anti-angiogenic effects, have shown only modest benefit in advanced and unresectable HCC [4]. Administration approved nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, to treat advanced HCC in patients who have been previously treated with sorafenib [5]. The evaluation of its clinical benefit is ongoing, indications suggest a degree of benefit for 18% of patients for this immunomodulatory drug. Combination therapy with atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF-A) has been associated with better outcomes, some patients experienced significant side effects [6]. There is growing evidence of immunological control of HCC, but still an urgent unmet need to develop new cancer therapies

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