肿瘤细胞治疗研究
英文原题：Proton pump inhibitor attenuates acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis.
Proton pump inhibitor attenuates acidic microenvironment to improve the therapeutic effects of MSLN-CAR-T cells on the brain metastasis.
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脑转移（BM）的发病率正逐渐升高，其预后和治疗效果均较差。
脑转移（BM）发生率逐渐上升，且患者预后和治疗效果较差。免疫疗法的出现为开发BM治疗方法带来了希望。本研究发现，与原发肿瘤相比，BM的肿瘤微环境（TME）更为“冷”且酸性更强，导致间皮素（MSLN）蛋白水平降低。MSLN是治疗伴BM的三阴性乳腺癌（TNBC）的CAR-T（CAR-T）细胞疗法的一个有前景靶点。上述因素可显著降低MSLN-CAR-T 细胞治疗TNBC脑转移的效能。按照临床最常用剂量给予泮托拉唑（PPZ），可显著提高TME的pH、抑制溶酶体活性、增加MSLN蛋白的膜表达水平，并在体外和体内增强MSLN-CAR-T 细胞的杀伤能力。在非小细胞肺癌脑转移模型中也获得类似结果。因此，与CAR-T 细胞联合使用时，能够提高靶抗原蛋白水平的PPZ可能构成治疗实体瘤脑转移的一种新型免疫治疗策略。
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.
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