E-Poster Presentation 34th Lorne Cancer Conference 2022

Inhibition of the dipeptidyl peptidase 4 enzyme family enhances CD8 T-cell recruitment and activates caspase 1 in a murine model of primary hepatocellular carcinoma (#302)

Mark D Gorrell 1 2 , James M Henderson 1 2 , Michelle SW Xiang 1 , Jiali C Huang 1 2 , Ben Roediger 1 , William W Bachovchin 3 , Jack H Lai 3 , Geoffrey W McCaughan 1 2 , Hui (Emma) E Zhang 1 2
  1. Liver Enzymes, Centenary Institute, University of Sydney, Sydney, NSW, Australia
  2. Faculty of Medicine and Health, University of Sydney, Sydney 2006, NSW, Australia
  3. Tufts University, Boston, MA, USA

About 85% of primary liver cancer is Hepatocellular Carcinoma (HCC), which has a 5-year survival rate below 20%. We recently reported that mRNA expression of the Dipeptidyl Peptidase 4 (DPP4) gene family is highly upregulated in human HCC tumours compared to non-diseased liver tissue, and is associated with poor survival in HCC patients [1]. Pan-DPP compounds, which inhibit all the DPP4 enzyme family, such as talabostat and ARI-4175, can mediate tumour regression by immune-mediated mechanisms [2] that are believed to include NLRP1 activation. NLRP1 activation is inhibited by DPP9 [3]. DPP4 dampens CXCR3 stimulation. This study 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 the concentration of activated caspase-1 in the HCC-bearing liver. Autophagy markers were unaffected. In summary, 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 [4].

  1. Huang, J. C., et al. (2021) DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma. Cancers 13, 1637
  2. Donahue, R. N., et al. (2014) A pan inhibitor of DASH family enzymes induces immunogenic modulation and sensitizes murine and human carcinoma cells to antigen-specific cytotoxic T lymphocyte killing: implications for combination therapy with cancer vaccines. Vaccine 32, 3223-3231
  3. Hollingsworth, L. R., et al. (2021) DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature 592, 778-783
  4. Henderson, J. M., et al (2021) Dipeptidyl Peptidase Inhibition Enhances CD8 T Cell Recruitment and Activates Intrahepatic Inflammasome in a Murine Model of Hepatocellular Carcinoma. Cancers 13, 5495