RT Journal Article
SR Electronic
T1 Targeting PPT1 with ezurpimtrostat sensitives liver tumor to immunotherapy by switching cold into hot microenvironments
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.01.18.524541
DO 10.1101/2023.01.18.524541
A1 Eloïne Bestion
A1 Madani Rachid
A1 Annemilaï Tijeras-Raballand
A1 Gael Roth
A1 Thomas Decaens
A1 Christelle Ansaldi
A1 Soraya Mezouar
A1 Eric Raymond
A1 Philippe Halfon
YR 2023
UL http://biorxiv.org/content/early/2023/01/20/2023.01.18.524541.abstract
AB 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.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 StatementE.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 reportPPT1Palmitoyl-protein thioesterase 1PD-1programmed death-1MHCmajor histocompatibility complexHCChepatocarcinomaICIimmune checkpoint inhibitorsWWeekCTCeliac TrunkHEShematoxylin-phloxin-saffronRTroom temperaturePBSphosphate-buffered salinePBMCPeripheral blood mononuclear cellIFNinterferonFBSfetal bovine serumNBR1neighbor of BRCA1 gene 1TAMtumor-associated macrophagePD-L1anti-programmed death-ligandCTLA-4anti-cytotoxic T-lymphocyte-associated protein