Ezurpimtrostat，一种棕榈酰-蛋白硫酯酶-1 抑制剂，与 PD-1 抑制联合使用可在肝细胞癌中重新产生 CD8 淋巴细胞。
Ezurpimtrostat, A Palmitoyl-Protein Thioesterase-1 Inhibitor, Combined with PD-1 Inhibition Provides CD8 Lymphocyte Repopulation in Hepatocellular Carcinoma.
机构信息
Genoscience Pharma, 10, Rue d'Iéna, 13006, Marseille, France.
AFR Oncologie, Boulogne-Billancourt, France.
出版信息
Target Oncol. 2024 Jan;19(1):95-106. doi: 10.1007/s11523-023-01019-8. Epub 2023 Dec 22.
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.
背景
棕榈酰蛋白硫酯酶 1（PPT1）是一种临床阶段可抑制癌症自噬的药物靶点。
目的
我们旨在确定使用 ezurpimtrostat 靶向 PPT1 的细胞和分子活性，同时联合使用抗 PD-1 抗体。
方法
在这项研究中，我们使用了一种转基因免疫功能正常的肝癌小鼠模型。
结果
在此，我们揭示了使用 ezurpimtrostat 抑制 PPT1 通过与抗程序性死亡-1（PD-1）联合使用诱导淋巴细胞渗透到肿瘤中，从而降低肝癌小鼠模型中的肝肿瘤负担。抑制 PPT1 通过增加肝癌细胞表面主要组织相容性复合体（MHC）-I 的表达，并通过重新定植和激活细胞毒性 CD8 淋巴细胞来调节免疫，从而增强抗 PD-1 免疫疗法的效果。
结论
ezurpimtrostat 将冷肿瘤转化为热肿瘤，因此可以改善肝癌的 T 细胞介导的免疫疗法。
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