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

Abstract

BackgroundPalmitoyl-protein thioesterase-1 (PPT1) is an exciting druggable target for inhibiting autophagy in cancer. MethodsIn 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. ResultsHerein, 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. ConclusionsEzurpimtrostat turns cold into hot tumors and, thus, constitutes a powerful strategy to improve T cell-mediated immunotherapies in liver cancer. Summary boxWe 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/524541v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1f44bf3org.highwire.dtl.DTLVardef@1a66ca8org.highwire.dtl.DTLVardef@127a51corg.highwire.dtl.DTLVardef@1c8f2af_HPS_FORMAT_FIGEXP M_FIG C_FIG Ezurpimtrostat activities in cancerThe 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.