Sialyl Tn-expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells
Sialyl Tn-expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells
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DOI：
10.1016/j.molonc.2014.02.008
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发表时间：
2014-05-01
影响因子：
6.6
通讯作者：
Videira, Paula A.
中科院分区：
文献类型：
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作者：
Carrascal, Mylene A.;Severino, Paulo F.;Videira, Paula A.
尽管广泛接受聚糖在免疫中起中心作用，但它们如何促进倾斜免疫应答仍然不清楚。在这项研究中，我们试图评估恶性表型相关聚糖，唾液酸-Tn（STn）在免疫反应的关键协调机制，树突状细胞（DC）的功能的影响。在高级别膀胱癌组织中，STn抗原显著过表达，并与ST 6 GALNAC 1唾液酸转移酶表达增加相关。呈现ST 6 GALNAC 1表达升高的膀胱癌组织显示与CD 1a（膀胱未成熟DC的标志物）表达增加相关，并且显示伴随的低水平的Th 1诱导细胞因子IL-12和TNF-α。在体外，与STn（+）膀胱癌细胞共孵育的人DC具有未成熟表型（MHC-II低、CD 80（低）和CD 86（低）），并且对进一步的成熟刺激无反应。当与STn（+）癌细胞接触时，DC表达显著降低的IL-12和TNF-α。与致耐受性DC谱一致，由用来源于STn（+）癌细胞的抗原脉冲的DC引发的T细胞未被活化，并显示FoxP 3（高）IFN-γ（低）表型。在STn（+）癌细胞中阻断STn抗原和STn（+）糖蛋白CD 44和MUC 1能够降低耐受的诱导，并且DCs变得更加成熟。总的来说，我们的数据表明，表达STn的癌细胞损害DC的成熟，并赋予DCs致耐受性功能，限制了它们触发保护性抗肿瘤T细胞应答的能力。STn抗原，特别是STn（+）糖蛋白是规避肿瘤诱导的致耐受性机制的潜在靶标。(C)2014年欧洲生物化学学会联合会。Elsevier B. V.出版，保留所有权利。
Despite the wide acceptance that glycans are centrally implicated in immunity, exactly how they contribute to the tilt immune response remains poorly defined. In this study, we sought to evaluate the impact of the malignant phenotype-associated glycan, sialyl-Tn (STn) in the function of the key orchestrators of the immune response, the dendritic cells (DCs). In high grade bladder cancer tissue, the STn antigen is significantly overexpressed and correlated with the increased expression of ST6GALNAC1 sialyltransferase. Bladder cancer tissue presenting elevated expression of ST6GALNAC1 showed a correlation with increased expression of CD1a, a marker for bladder immature DCs and showed concomitant low levels of Th1-inducing cytokines IL-12 and TNF-alpha. In vitro, human DCs co-incubated with STn(+) bladder cancer cells, had an immature phenotype (MHC-IIlow, CD80(low) and CD86(low)) and were unresponsive to further maturation stimuli. When contacting with STn(+) cancer cells, DCs expressed significantly less IL-12 and TNF-alpha. Consistent with a tolerogenic DC profile, T cells that were primed by DCs pulsed with antigens derived from STn(+) cancer cells were not activated and showed a FoxP3(high) IFN-gamma(low) phenotype. Blockade of STn antigens and of STn(+) glycoprotein, CD44 and MUC1, in STn(+) cancer cells was able to lower the induction of tolerance and DCs become more mature.Overall, our data suggest that STn-expressing cancer cells impair DC maturation and endow DCs with a tolerogenic function, limiting their capacity to trigger protective antitumour T cell responses. STn antigens and, in particular, STn(+) glycoproteins are potential targets for circumventing tumour-induced tolerogenic mechanisms. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.