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. Centenary Institute, Sydney, NSW, Australia
  2. University of Sydney, Newtown, 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