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.

中文翻译：

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质子泵抑制剂减弱酸性微环境，提高 MSLN-CAR-T 细胞对脑转移的治疗效果


脑转移 （BM） 的发生率逐渐增加，预后和治疗效果较差。免疫疗法的出现为 BM 治疗的发展带来了希望。这项研究表明，与原发性癌症相比，BMs 具有更冷、更酸性的肿瘤微环境 （TME），导致间皮素 （MSLN） 蛋白水平降低，这是嵌合抗原受体-T （CAR-T） 细胞治疗三阴性乳腺癌 （TNBC） 伴 BMs的有前途的靶点。这些因素可以显着降低 TNBC BMs 中 MSLN-CAR-T 细胞的效率。临床上最常用的泮托拉唑 （PPZ） 给药显着增加了 TME 的 pH 值，抑制了溶酶体活性，增加了 MSLN 蛋白的膜水平，并提高了 MSLN-CAR-T 细胞在 体外和 体内的杀伤能力。在非小细胞肺癌 BMs 中也获得了类似的结果。因此，当与 CAR-T 细胞联合给药时，增加靶抗原蛋白水平的 PPZ 可能构成一种用 BMs 治疗实体瘤的新免疫治疗策略。