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Ezurpimtrostat, A Palmitoyl-Protein Thioesterase-1 Inhibitor, Combined with PD-1 Inhibition Provides CD8+ Lymphocyte Repopulation in Hepatocellular Carcinoma

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Abstract

Background

Palmitoyl-protein thioesterase-1 (PPT1) is a clinical stage druggable target for inhibiting autophagy in cancer.

Objective

We aimed to determine the cellular and molecular activity of targeting PPT1 using ezurpimtrostat, in combination with an anti-PD-1 antibody.

Methods

In this study we used a transgenic immunocompetent mouse model of hepatocellular carcinoma.

Results

Herein, we revealed that inhibition of PPT1 using ezurpimtrostat decreased the liver tumor burden in a mouse model of hepatocellular carcinoma by inducing the penetration of lymphocytes into 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 tumors into hot tumors and, thus, could improve T cell-mediated immunotherapies in liver cancer.

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Author information

Author notes

  1. Eloïne Bestion, Madani Rachid, Annemilaï Tijeras-Raballand, Soraya Mezouar, Eric Raymond, Philippe Halfon have contributed equally.

Authors and Affiliations

  1. Genoscience Pharma, 10, Rue d’Iéna, 13006, Marseille, France

    Eloïne Bestion, Madani Rachid, Christelle Ansaldi, Soraya Mezouar, Eric Raymond & Philippe Halfon

  2. AFR Oncologie, Boulogne-Billancourt, France

    Annemilaï Tijeras-Raballand

  3. Centre hospitalouniversitaire Grenoble Alpes/Institute for Advanced Biosciences, Centre national de la recherché scienti-fique, Unité mixte de recherche 5309-Institut national de la santé et de la recherche médicale U1209, University Grenoble Alpes/Hepato-Gastroenterology and Digestive Oncology Department, 38043, Grenoble, France

    Gael Roth & Thomas Decaens

  4. Etablissement français du sang, Centre national de la recherche scientifique, Anthropologie bio-culturelle, droit, éthique et santé, “Biologie des Groupes Sanguins”, Aix-Marseille University, Marseille, France

    Soraya Mezouar

  5. Oncology Department, Groupe Hospitalier Paris Saint Joseph, Paris, France

    Eric Raymond

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  1. Eloïne Bestion
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Corresponding author

Correspondence to Philippe Halfon.

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Funding

Genoscience Pharma.

Conflicts of Interest/Competing Interests

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 that might be relevant to the contents of this manuscript.

Ethics Approval

All experiments were performed following Directive 2010/63/EU of the European Parliament and Council on September 22, 2010. This project was approved by the local ethic committee (Comité d’éthique en experimentation animale Lariboisière-Villemin n°9).

Consent to Participate

Not applicable.

Consent for Publication

All authors have approved the last version of the manuscript and its future publication.

Availability of Data and Material

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Code Availability

Not applicable.

Authors’ Contributions

Conception and design: EB, MR, AT-R, SM. Data analysis: EB, MR, SM. Study supervision: MR, EB, SM, PH. Writing, review of the manuscript: MR, EB, GR, TD, CA, SM, ER, PH.

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Bestion, E., Rachid, M., Tijeras-Raballand, A. et al. Ezurpimtrostat, A Palmitoyl-Protein Thioesterase-1 Inhibitor, Combined with PD-1 Inhibition Provides CD8+ Lymphocyte Repopulation in Hepatocellular Carcinoma. Targ Oncol 19, 95–106 (2024). https://doi.org/10.1007/s11523-023-01019-8

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  • DOI: https://doi.org/10.1007/s11523-023-01019-8

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