Proton pump inhibitor attenuates acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis.

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Xuejia Zhai, Ling Mao, Qingmei Kang, Jie Liu, Yu Zhou, Jun Wang, Xianyan Yang, Di Wang, Junhan Wang, Yao Li, Jiangjie Duan, Tao Zhang, Shuang Lin, Tingting Zhao, Jianjun Li, Min Wu, Shicang Yu
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Abstract

The incidence of brain metastasis (BM) is gradually increasing, and the prognosis and therapeutic effect are poor. The emergence of immunotherapy has brought hope for the development of BM treatments. This study revealed that compared with primary cancers, BMs have a colder and more acidic tumor microenvironment (TME), resulting in reduced protein levels of mesothelin (MSLN), a promising target for chimeric antigen receptor-T (CAR-T) cell therapy for triple-negative breast cancer (TNBC) with BMs. These factors could significantly decrease the efficiency of MSLN-CAR-T cells in TNBC BMs. Pantoprazole (PPZ) administration at the most commonly used dose in the clinic notably increased the pH of the TME, inhibited lysosomal activity, increased the membrane levels of the MSLN protein and improved the killing ability of MSLN-CAR-T cells both in vitro and in vivo. Similar results were obtained in non-small cell lung cancer BMs. Hence, when administered in combination with CAR-T cells, PPZ, which increases the protein levels of target antigens, may constitute a new immunotherapeutic strategy for treating solid tumors with BMs.

质子泵抑制剂可改善酸性微环境,从而提高 MSLN-CAR-T 细胞对实体瘤脑转移的治疗效果。
脑转移(BM)的发病率逐渐升高,预后和治疗效果都很差。免疫疗法的出现为脑转移瘤治疗的发展带来了希望。这项研究发现,与原发性癌症(PC)相比,脑转移瘤的肿瘤微环境(TME)更 "冷"、更酸性,导致间皮素(MSLN)蛋白水平降低,而间皮素是嵌合抗原受体-T(CAR-T)细胞治疗三阴性乳腺癌(TNBC)脑转移瘤的一个有希望的靶点。这些因素可能会大大降低MSLN-CAR-T细胞在TNBC母细胞中的效率。以临床上最常用的剂量服用泮托拉唑(PPZ)可显著提高TME的pH值,抑制溶酶体活性,增加MSLN蛋白的膜水平,并提高MSLN-CAR-T细胞在体外和体内的杀伤能力。在非小细胞肺癌(NSCLC)骨髓细胞中也得到了类似的结果。因此,当PPZ与CAR-T细胞联合给药时,它能提高靶抗原的蛋白水平,可能会成为治疗有BM的实体瘤的一种新的免疫治疗策略。
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
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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