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MTH1抑制可减轻免疫抑制并增强抗PD-L1免疫疗法在实验性间皮瘤中的疗效。

MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma.

作者信息

Magkouta Sophia F, Vaitsi Photene C, Iliopoulou Marianthi P, Pappas Apostolos G, Kosti Chrysavgi N, Psarra Katherina, Kalomenidis Ioannis T

机构信息

"Marianthi Simou Laboratory", 1st Department of Critical Care and Pulmonary Medicine, Evangelismos Hospital, School of Medicine, National and Kapodistrian University of Athens 10676 Athens, Greece.

Department of Immunology-Histocompatibility, Evangelismos Hospital, 10675 Athens, Greece.

出版信息

Cancers (Basel). 2023 Oct 12;15(20):4962. doi: 10.3390/cancers15204962.

DOI:10.3390/cancers15204962
PMID:37894329
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10605650/
Abstract

BACKGROUND

MTH1 protects tumor cells and their supporting endothelium from lethal DNA damage triggered by oxidative stress in the tumor microenvironment, thus promoting tumor growth. The impact of MTH1 on the tumor-related immune compartment remains unknown. We hypothesized that MTH1 regulates immune fitness and therefore enhances the activity of currently used immunotherapeutic regimens.

METHODS

Our hypotheses were validated in two syngeneic murine mesothelioma models using the clinically relevant MTH1 inhibitor, karonudib. We also examined the effect of combined MTH1 and PD-L1 blockade in mesothelioma progression, focusing on the main immune players.

RESULTS

Karonudib administration enhances M1 macrophage polarization, stimulates CD8 expansion and promotes the activation of DC and T cells. Combined administration of PD-L1 and MTH1 inhibitors impairs mesothelioma tumor growth and mesothelioma-associated pleural effusion accumulation more effectively compared to each monotherapy.

CONCLUSIONS

Combined MTH1 and PD-L1 inhibition holds promise for the successful clinical management of mesothelioma.

摘要

背景

MTH1可保护肿瘤细胞及其支持性内皮细胞免受肿瘤微环境中氧化应激引发的致死性DNA损伤，从而促进肿瘤生长。MTH1对肿瘤相关免疫区室的影响尚不清楚。我们推测MTH1调节免疫适应性，因此增强了目前使用的免疫治疗方案的活性。

方法

我们使用临床相关的MTH1抑制剂卡诺地布在两种同基因小鼠间皮瘤模型中验证了我们的假设。我们还研究了联合阻断MTH1和PD-L1对间皮瘤进展的影响，重点关注主要的免疫细胞。

结果

给予卡诺地布可增强M1巨噬细胞极化，刺激CD8细胞扩增，并促进DC和T细胞的激活。与单一疗法相比，联合使用PD-L1和MTH1抑制剂更有效地抑制间皮瘤肿瘤生长和间皮瘤相关胸腔积液的积聚。

结论

联合抑制MTH1和PD-L1有望成功临床治疗间皮瘤。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/bc2f5e9d0811/cancers-15-04962-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/1db981817306/cancers-15-04962-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/f9cce6980e8f/cancers-15-04962-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/56b9e9568404/cancers-15-04962-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/bc2f5e9d0811/cancers-15-04962-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/1db981817306/cancers-15-04962-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/f9cce6980e8f/cancers-15-04962-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/56b9e9568404/cancers-15-04962-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cf20/10605650/bc2f5e9d0811/cancers-15-04962-g004.jpg

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