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

IF 4.4 3区医学 Q2 ONCOLOGY Targeted Oncology Pub Date : 2024-01-01 Epub Date: 2023-12-22 DOI:10.1007/s11523-023-01019-8

Eloïne Bestion, Madani Rachid, Annemilaï Tijeras-Raballand, Gael Roth, Thomas Decaens, Christelle Ansaldi, Soraya Mezouar, Eric Raymond, Philippe Halfon

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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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棕榈酰蛋白硫酯酶-1抑制剂Ezurpimtrostat与PD-1抑制剂联合使用可使肝细胞癌中的CD8+淋巴细胞重新增殖。

背景：棕榈酰蛋白硫酯酶-1（PPT1）是抑制癌症自噬的临床药物靶点：棕榈酰蛋白硫酯酶-1（PPT1）是抑制癌症自噬的临床阶段药物靶点：我们的目的是确定使用依佐匹克与抗PD-1抗体联合靶向PPT1的细胞和分子活性：在这项研究中，我们使用了转基因免疫功能正常的肝细胞癌小鼠模型：结果：我们发现，在肝细胞癌小鼠模型中，使用依佐普仑司坦抑制PPT1与抗程序性死亡-1（PD-1）联合治疗时，可通过诱导淋巴细胞穿透肿瘤减轻肝脏肿瘤负担。通过增加肝癌细胞表面主要组织相容性复合物（MHC）-I的表达，抑制PPT1可增强抗PD-1免疫疗法的效果，并通过细胞毒性CD8+淋巴细胞的再定植和活化调节免疫力：结论：依唑吡坦能将冷瘤变为热瘤，从而改善肝癌中T细胞介导的免疫疗法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Targeted Oncology 医学-肿瘤学

CiteScore

8.40

自引率

3.70%

发文量

审稿时长

>12 weeks

期刊介绍： Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.