Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes.
Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes.
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血浆凝胶素通过重置巨噬细胞亚型的相对丰度和功能来赋予卵巢癌的化学抗性。
DOI：
10.3390/cancers14041039
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发表时间：
2022-02-18
期刊：
影响因子：
5.2
通讯作者：
Tsang BK
中科院分区：
文献类型：
--
作者：
Asare-Werehene M;Tsuyoshi H;Zhang H;Salehi R;Chang CY;Carmona E;Librach CL;Mes-Masson AM;Chang CC;Burger D;Yoshida Y;Tsang BK
卵巢癌是最致命的女性癌症之一，生存率极低，主要是由于诊断晚，复发和耐药性。虽然血浆凝溶胶蛋白（pGSN）的过表达保护卵巢癌细胞免受化疗诱导的死亡，但其在肿瘤微环境中的免疫作用较少被探索。在这里，我们证明了pGSN过表达下调M1巨噬细胞的抗肿瘤功能，这种作用导致化疗耐药性和患者生存率低下。这项研究证明了pGSN对肿瘤浸润的M1巨噬细胞的新型抑制作用，并为最大限度地提高卵巢癌患者免疫治疗的有效性提供了新的见解。卵巢癌（OVCA）是最致命的妇科癌症，5年生存率低于50%。尽管有新的治疗策略，如免疫检查点阻断剂（ICB），但肿瘤复发和耐药性仍然是实现长期治疗成功的关键障碍。因此，迫切需要了解化学抗性OVCA中免疫失调的细胞机制，以利用宿主的免疫系统来改善存活率。血浆凝溶胶蛋白（pGSN）mRNA的过度表达与OVCA患者的预后较差相关;然而，其免疫调节作用尚未阐明。在这项研究中，我们首次报道了pGSN作为M1巨噬细胞抗肿瘤功能的抑制剂在OVCA化疗耐药性中的作用。上皮pGSN表达增加与化疗反应性丧失和生存率低相关。虽然M1巨噬细胞浸润增加的患者由于OVCA细胞中一氧化氮诱导的ROS积累而表现出更好的存活率，但存活率差的队列具有更高的M2巨噬细胞浸润。有趣的是，上皮pGSN表达增加与浸润的M1巨噬细胞的存活益处降低显著相关，通过caspase-3活化增加和iNOS和TNFα产生减少导致细胞凋亡。此外，上皮pGSN表达是预测无进展生存期的独立预后标志物。这些发现支持了我们的假设，即pGSN是炎症的调节剂，并在OVCA中赋予化学抗性，部分通过重置卵巢肿瘤微环境中巨噬细胞亚型的相对丰度和功能。我们的研究结果提高了pGSN可能是OVCA免疫介导的化疗耐药性的潜在治疗靶点的可能性。
Ovarian cancer is one of the deadliest female cancers with very poor survival, primarily due to late diagnosis, recurrence and chemoresistance. Although the over-expression of plasma gelsolin (pGSN) protects ovarian cancer cells from chemotherapy-induced death, its immunological role in the tumor microenvironment is less explored. Here, we demonstrate that pGSN over-expression downregulates the anti-tumor functions of M1 macrophages, an effect that contributes to chemoresistance and poor patient survival. This study demonstrates the novel inhibitory role of pGSN on tumor-infiltrated M1 macrophages and also offers new insights in maximizing the effectiveness of immunotherapy for ovarian cancer patients. Ovarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, there is an urgent need to understand the cellular mechanisms of immune dysregulation in chemoresistant OVCA in order to harness the host’s immune system to improve survival. The over-expression of plasma gelsolin (pGSN) mRNA is associated with a poorer prognosis in OVCA patients; however, its immuno-modulatory role has not been elucidated. In this study, for the first time, we report pGSN as an inhibitor of M1 macrophage anti-tumor functions in OVCA chemoresistance. Increased epithelial pGSN expression was associated with the loss of chemoresponsiveness and poor survival. While patients with increased M1 macrophage infiltration exhibited better survival due to nitric-oxide-induced ROS accumulation in OVCA cells, cohorts with poor survival had a higher infiltration of M2 macrophages. Interestingly, increased epithelial pGSN expression was significantly associated with the reduced survival benefits of infiltrated M1 macrophages, through apoptosis via increased caspase-3 activation and reduced production of iNOS and TNFα. Additionally, epithelial pGSN expression was an independent prognostic marker in predicting progression-free survival. These findings support our hypothesis that pGSN is a modulator of inflammation and confers chemoresistance in OVCA, in part by resetting the relative abundance and function of macrophage subtypes in the ovarian tumor microenvironment. Our findings raise the possibility that pGSN may be a potential therapeutic target for immune-mediated chemoresistance in OVCA.
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影响因子：
7.3
作者：
Diskin C;Pålsson-McDermott EM
通讯作者：
Pålsson-McDermott EM
影响因子：
46.9
作者：
Choi, Bryan D.;Yu, Xiaoling;Maus, Marcela V.
通讯作者：
Maus, Marcela V.
DOI：
10.1073/pnas.1401166111
发表时间：
2014-10-07
影响因子：
11.1
作者：
Abedini, Mohammad R.;Wang, Pei-Wen;Tsang, Benjamin K.
通讯作者：
Tsang, Benjamin K.
影响因子：
11.2
作者：
Asare-Werehene, Meshach;Communal, Laudine;Tsang, Benjamin K.
通讯作者：
Tsang, Benjamin K.
影响因子：
2.4
作者：
Guo Y;Zhang H;Xing X;Wang L;Zhang J;Yan L;Zheng X;Zhang M
通讯作者：
Zhang M