"T"eeing Up A Novel Therapy for Lymphangioleiomyomatosis.
"T"eeing Up A Novel Therapy for Lymphangioleiomyomatosis.
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“T”准备一种治疗淋巴管平滑肌瘤病的新疗法。
DOI：
10.1165/rcmb.2020-0049ed
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发表时间：
2020
影响因子：
6.4
通讯作者：
Owen,CarolineA
中科院分区：
文献类型：
--
作者：
Wang,Xiaoyun;Rojas-Quintero,Joselyn;Owen,CarolineA
散发性淋巴管平滑肌瘤病（s-LAM）是一种罕见的多系统肿瘤性疾病，几乎只影响绝经前妇女（1）。第二种形式的LAM发生在高达30-40%的女性和z12%的男性结节性硬化症（TSCLAM）（2）。患有s-LAM的女性表现为运动时进行性呼吸困难、复发性气胸、乳糜胸和腹腔积液以及胸和腹腔肿瘤（包括淋巴管平滑肌瘤和血管平滑肌脂肪瘤）（3）。LAM细胞是该病的组织病理学标志，来源于肺外，通过循环和呼吸道扩散到肺和其他器官。LAM细胞表达淋巴管生成生长因子（血管内皮生长因子[VEGF]-C和VEGF-D），诱导肺中淋巴管形成紊乱，这沿着LAM细胞高水平表达蛋白酶，可能导致肺重塑和囊性肺破坏（4，5）。LAM肺结节含有内部纺锤形的表达α-肌动蛋白的平滑肌样细胞，并被上皮样多边形细胞包围，这些细胞表达大量的黑素细胞标志物，包括gp 100，这是一种跨膜糖蛋白（5，6）。LAM是由两种肿瘤抑制基因之一的功能缺失突变引起的，TSC 1（hamartin）和TSC 2（tuberin）（2，7）。TSC 1和TSC 2与TBC 1D 7（Tre 2-Bub 2-Cdc 16 [TBC]-1结构域家族成员7）形成复合物，其抑制mTOR的活化。TSC 1或TSC 2基因的功能缺失突变导致mTOR信号转导的不受控制的激活，这诱导肿瘤样LAM细胞的增殖（图1）（2）。mTOR抑制剂西罗莫司（雷帕霉素）在美国被批准用于治疗LAM患者。在临床试验中，西罗莫司稳定肺功能，改善LAM患者的生活质量和功能能力（8）。然而，西罗莫司与显著的毒性相关，并且缺乏长期安全性和有效性数据。因此，对于LAM的更安全和有效的疗法存在未满足的需求。在本期杂志上报道的一项研究中，Han及其同事（pp. 793-804）通过评估一种高度创新的免疫疗法来解决这个问题（9）。这种策略的基本原理是基于这样的事实，即LAM细胞在体外对T细胞介导的毒性敏感（10，11），但LAM肿瘤缺乏浸润性T细胞，并表达免疫检查点抑制剂，如PD-L1（程序性细胞死亡配体-1）（12）。选择GP 100作为靶抗原是因为LAM肿瘤中的上皮样细胞表达高水平的这种蛋白质（其仅由健康受试者中的黑素细胞表达）。作者使用了多阶段
Sporadic lymphangioleiomyomatosis (s-LAM) is a rare multisystem, neoplastic disease that almost exclusively affects premenopausal women (1). A second form of LAM occurs in up to 30-40% of women and z12% of men with tuberous sclerosis complex (TSCLAM)(2). Women with s-LAM present with progressive dyspnea upon exertion, recurrent pneumothorax, chylous thoracic and abdominal effusions, and thoracic and abdominal tumors (including lymphangioleiomyomas and angiomyolipomas)(3). Progressive respiratory failure leading to death occurs if the disease is not treated.LAM cells, the histopathological hallmark of the disease, arise from an unknown extrapulmonary source and spread to the lung and other organs via the circulation and lymphatics. LAM cells express lymphangiogenic growth factors (vascular endothelial growth factor [VEGF]-C and VEGF-D) that induce disordered lymphatic channel formation in the lung, which, along with highlevel expression of proteinases by LAM cells, likely contributes to lung remodeling and cystic lung destruction (4, 5). LAM pulmonary nodules contain inner spindle-shaped a-actin-expressing smooth muscle-like cells and are surrounded by epithelioid polygonal cells that express high amounts of melanocyte markers, including gp100, which is a transmembrane glycoprotein (5, 6). LAM is caused by loss-of-function mutations in one of two tumor suppressor genes, TSC1 (hamartin) and TSC2 (tuberin)(2, 7). TSC1 and TSC2 form a complex with TBC1D7 (Tre2-Bub2-Cdc16 [TBC]-1 domain family member 7), which inhibits activation of mTOR. Loss-of-function mutations in the TSC1 or TSC2 gene lead to uncontrolled activation of mTOR signaling, which induces the proliferation of tumor-like LAM cells (Figure 1)(2). The mTOR inhibitor sirolimus (rapamycin) is approved to treat patients with LAM in the United States. In clinical trials, sirolimus stabilized lung function and improved the quality of life and functional capacity of patients with LAM (8). However, sirolimus is associated with significant toxicities, and long-term safety and efficacy data are lacking. Thus, there is an unmet need for more safe and effective therapies for LAM. In a study reported in this issue of the Journal, Han and colleagues (pp. 793-804) tackled this issue by evaluating a highly innovative immunotherapy approach (9). The rationale for this strategy was based on the fact that LAM cells are susceptible to T-cell-mediated toxicity in vitro (10, 11), but LAM tumors are devoid of infiltrating T cells and express immune checkpoint inhibitors such as PD-L1 (programmed cell death ligand-1)(12). GP100 was selected as the target antigen because epithelioid cells in LAM tumors express high levels of this protein (which is only expressed by melanocytes in healthy subjects). The authors used a multistage