Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade.
Extracellular Vesicles Present in Human Ovarian Tumor Microenvironments Induce a Phosphatidylserine-Dependent Arrest in the T-cell Signaling Cascade.
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DOI：
10.1158/2326-6066.cir-15-0086
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发表时间：
2015-11
影响因子：
10.1
通讯作者：
Bankert RB
中科院分区：
文献类型：
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作者：
Kelleher RJ Jr;Balu-Iyer S;Loyall J;Sacca AJ;Shenoy GN;Peng P;Iyer V;Fathallah AM;Berenson CS;Wallace PK;Tario J;Odunsi K;Bankert RB
人类肿瘤微环境中免疫抑制因子的鉴定以及阻断这些因子的能力有望增强患者的抗肿瘤免疫应答。我们先前已证实，卵巢肿瘤腹水中存在一种未鉴定的因子，通过阻止T细胞信号级联反应可逆地抑制T细胞的活化。肿瘤腹水液的超离心现在已经揭示了含有平均直径为80nm的小细胞外囊泡（EV）的颗粒。T细胞停滞被确定为与存在于囊泡双层的外小叶上的磷脂酰丝氨酸（PS）因果相关，因为表达EV的PS的耗尽或用抗PS抗体阻断PS显著抑制囊泡诱导的信号传导停滞。还从实体瘤组织中分离出抑制性EV。卵巢肿瘤微环境中免疫抑制囊泡的存在以及我们阻断其抑制T细胞功能的能力代表了卵巢癌患者的潜在治疗靶点。
The identification of immunosuppressive factors within human tumor microenvironments, and the ability to block these factors, would be expected to enhance patients’ anti-tumor immune responses. We previously established that an unidentified factor, or factors, present in ovarian tumor ascites fluids reversibly inhibited the activation of T cells by arresting the T cell signaling cascade. Ultracentrifugation of the tumor ascites fluid has now revealed a pellet that contains small extracellular vesicles (EV) with an average diameter of 80nm. The T cell arrest was determined to be causally linked to phosphatidylserine (PS) that is present on the outer leaflet of the vesicle bilayer, as a depletion of PS expressing EV or a blockade of PS with anti-PS antibody significantly inhibits the vesicle induced signaling arrest. The inhibitory EV were also isolated from solid tumor tissues. The presence of immune suppressive vesicles in the microenvironments of ovarian tumors and our ability to block their inhibition of T cell function represent a potential therapeutic target for patients with ovarian cancer.