Targeting PPT1 with ezurpimtrostat sensitives liver tumor to immunotherapy by switching cold into hot microenvironments

Background Palmitoyl-protein thioesterase-1 (PPT1) is an exciting druggable target for inhibiting autophagy in cancer. Methods In this study, we aimed to evaluate the effects of ezurpimtrostat-targeting PPT1 in combination with an anti-PD-1 antibody in liver cancer using a transgenic immunocompetent mouse model. Results Herein, we revealed that inhibition of PPT1 using ezurpimtrostat, a safe anticancer drug in humans, decreased the liver tumor burden by inducing the penetration of lymphocytes within tumors when combined with anti-programmed death-1 (PD-1). Inhibition of PPT1 potentiates the effects of anti-PD-1 immunotherapy by increasing the expression of major histocompatibility complex (MHC)-I at the surface of liver cancer cells and modulates immunity through recolonization and activation of cytotoxic CD8+ lymphocytes. Conclusions Ezurpimtrostat turns cold into hot tumors and, thus, constitutes a powerful strategy to improve T cell-mediated immunotherapies in liver cancer. Summary box We reported that inhibiting palmitoyl-protein thioesterase-1 enzyme (PPT1) enhances the antitumor activity of anti-programmed death-1 (PD-1) in liver cancer in preclinical models. This study provides the rational for this combination in cancer clinical trials. ![Figure][1] Ezurpimtrostat activities in cancer The absence of immune effectors especially cytotoxic cells in the microenvironment of cold tumor is associated with a lack of response to ICI. This condition is mainly due to an increase in the autophagy process responsible for the sequestration and destruction of an antigen-presenting molecule, MHC-I. The inhibition of PPT1 using ezurpimtrostat treatment led to ( 1 ) the inhibition of PPT1 and consequently the autophagy process, ( 2 ) the increase of MHC-I surface expression, and ( 3 ) the recruitment and the activation of CD8+ T cells at tumor site leading to ( 4 ) the improvement of CD8+ T cell cytotoxic activity. Thus, ezurpimtrostat-treated tumors become eligible for anti-PD-1 immunotherapy as the combination of both led to decreased macronodules, micronodules, and tumor growth. ### Competing Interest Statement E.B, M.R, S.M, C.A, E.R and P.H are employees of Genoscience Pharma. E.R and P.H are shareholders of Genoscience Pharma. A.T.R has no conflict of interest to report * PPT1 : Palmitoyl-protein thioesterase 1 PD-1 : programmed death-1 MHC : major histocompatibility complex HCC : hepatocarcinoma ICI : immune checkpoint inhibitors W : Week CT : Celiac Trunk HES : hematoxylin-phloxin-saffron RT : room temperature PBS : phosphate-buffered saline PBMC : Peripheral blood mononuclear cell IFN : interferon FBS : fetal bovine serum NBR1 : neighbor of BRCA1 gene 1 TAM : tumor-associated macrophage PD-L1 : anti-programmed death-ligand CTLA-4 : anti-cytotoxic T-lymphocyte-associated protein [1]: pending:yes