{"title":"Targeting SNCA in the treatment of malignant ascites in gastrointestinal cancer","authors":"","doi":"10.1016/j.tranon.2024.102075","DOIUrl":null,"url":null,"abstract":"<div><p>Peritoneal tumor dissemination and subsequent malignant tumor ascites (MTA) occur unexpectedly and repeatedly in patients with gastrointestinal (GI) cancers, and worsen quality of life and prognosis of the patients. Various treatments have been clinically developed for these patients, while most of the MTA cases are refractory to the treatments. Thus, effective treatments are urgently needed to improve the clinical outcomes. In this study, we identified α-synuclein (SNCA) as an immunological determinant of MTA progression in GI cancer through translational research using mouse tumor models and clinical specimens collected from gastric cancer patients. We found that the SNCA<sup>+</sup> subsets were significantly increased in CD3<sup>+</sup> T cells, CD56<sup>+</sup> NK cells, and CD11b<sup>+</sup> myeloid cells within MTA and peripheral blood cells (PBCs) of MTA cases, albeit almost absent in PBCs of healthy donors, and spleen of naive mice. Of note, the SNCA<sup>+</sup> T-cell subset was rarely seen in patients that intraperitoneal lavage fluid without tumor cells was collected before surgery as a tumor-free control, suggesting a possible cancer-induced product, especially within the peritoneal cavity. In vivo treatment with anti-SNCA blocking mAb significantly induced anti-tumor effects in mouse MTA models, and synergistically improved anti-PD1 therapeutic efficacy, providing a significantly better prognosis. These suggest that SNCA is involved in severe immunosuppression in the MTA cases, and that blocking SNCA is effective in dramatically improving the immune status in the hosts. Targeting SNCA will be a promising strategy to improve clinical outcomes in the treatment of GI cancer patients, especially with MTA.</p></div>","PeriodicalId":48975,"journal":{"name":"Translational Oncology","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S193652332400202X/pdfft?md5=5bd38bce1831a8da1a5d032201f80726&pid=1-s2.0-S193652332400202X-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Translational Oncology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S193652332400202X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
Peritoneal tumor dissemination and subsequent malignant tumor ascites (MTA) occur unexpectedly and repeatedly in patients with gastrointestinal (GI) cancers, and worsen quality of life and prognosis of the patients. Various treatments have been clinically developed for these patients, while most of the MTA cases are refractory to the treatments. Thus, effective treatments are urgently needed to improve the clinical outcomes. In this study, we identified α-synuclein (SNCA) as an immunological determinant of MTA progression in GI cancer through translational research using mouse tumor models and clinical specimens collected from gastric cancer patients. We found that the SNCA+ subsets were significantly increased in CD3+ T cells, CD56+ NK cells, and CD11b+ myeloid cells within MTA and peripheral blood cells (PBCs) of MTA cases, albeit almost absent in PBCs of healthy donors, and spleen of naive mice. Of note, the SNCA+ T-cell subset was rarely seen in patients that intraperitoneal lavage fluid without tumor cells was collected before surgery as a tumor-free control, suggesting a possible cancer-induced product, especially within the peritoneal cavity. In vivo treatment with anti-SNCA blocking mAb significantly induced anti-tumor effects in mouse MTA models, and synergistically improved anti-PD1 therapeutic efficacy, providing a significantly better prognosis. These suggest that SNCA is involved in severe immunosuppression in the MTA cases, and that blocking SNCA is effective in dramatically improving the immune status in the hosts. Targeting SNCA will be a promising strategy to improve clinical outcomes in the treatment of GI cancer patients, especially with MTA.
腹膜肿瘤扩散和随后的恶性肿瘤腹水(MTA)在胃肠道(GI)癌症患者中意外和反复发生,使患者的生活质量和预后恶化。临床上已开发出针对这些患者的各种治疗方法,但大多数 MTA 病例对这些治疗方法无效。因此,迫切需要有效的治疗方法来改善临床疗效。在本研究中,我们利用小鼠肿瘤模型和胃癌患者的临床标本进行转化研究,发现α-突触核蛋白(SNCA)是消化道癌症MTA进展的免疫决定因素。我们发现,在 MTA 和 MTA 病例的外周血细胞(PBCs)中,CD3+ T 细胞、CD56+ NK 细胞和 CD11b+ 髓系细胞中的 SNCA+ 亚群明显增加,而健康供体的 PBCs 和天真小鼠的脾脏中几乎没有 SNCA+ 亚群。值得注意的是,手术前收集的腹腔灌洗液中没有肿瘤细胞,作为无肿瘤对照的患者很少出现 SNCA+ T 细胞亚群,这表明可能是癌症诱导的产物,尤其是在腹腔内。在小鼠 MTA 模型中,用抗 SNCA 阻断 mAb 进行体内治疗可显著诱导抗肿瘤作用,并协同提高抗 PD1 的疗效,从而明显改善预后。这表明,SNCA 参与了 MTA 病例中的严重免疫抑制,而阻断 SNCA 可以有效地显著改善宿主的免疫状态。以 SNCA 为靶点将是改善消化道癌症患者(尤其是 MTA 患者)临床治疗效果的一种有前途的策略。
期刊介绍:
Translational Oncology publishes the results of novel research investigations which bridge the laboratory and clinical settings including risk assessment, cellular and molecular characterization, prevention, detection, diagnosis and treatment of human cancers with the overall goal of improving the clinical care of oncology patients. Translational Oncology will publish laboratory studies of novel therapeutic interventions as well as clinical trials which evaluate new treatment paradigms for cancer. Peer reviewed manuscript types include Original Reports, Reviews and Editorials.