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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.
摘要：
在胃肠道（GI）癌症患者中，腹膜肿瘤播散和随后的恶性肿瘤腹水（MTA）意外和重复发生。并恶化患者的生活质量和预后。临床上已经为这些患者开发了各种治疗方法，而大多数MTA病例是难以治疗的。因此，迫切需要有效的治疗方法来改善临床结局.在这项研究中,通过使用小鼠肿瘤模型和胃癌患者临床标本进行的转化研究,我们确定α-突触核蛋白(SNCA)是GI癌中MTA进展的免疫学决定因素.我们发现在CD3+T细胞中SNCA+亚群显著增加,CD56+NK细胞，MTA和MTA病例的外周血细胞（PBCs）中的CD11b+骨髓细胞，尽管在健康捐赠者的PBC中几乎不存在，和幼稚小鼠的脾脏。值得注意的是，SNCA+T细胞亚群在手术前收集无肿瘤细胞的腹腔灌洗液作为无瘤对照的患者中很少见，提示一种可能的癌症诱导产物，尤其是在腹膜腔内。抗SNCA阻断mAb在小鼠MTA模型中的体内治疗显著诱导抗肿瘤作用,协同改善抗PD1治疗效果，提供明显更好的预后。这些表明SNCA与MTA病例中的严重免疫抑制有关，阻断SNCA可以有效地改善宿主的免疫状态。靶向SNCA将是一个有希望的策略，以改善胃肠道癌症患者的临床治疗结果，尤其是MTA。
