Glycosylation Status of CD43 Protein Is Associated with Resistance of Leukemia Cells to CTL-Mediated Cytolysis.
Glycosylation Status of CD43 Protein Is Associated with Resistance of Leukemia Cells to CTL-Mediated Cytolysis.
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DOI：
10.1371/journal.pone.0152326
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hosen N
中科院分区：
文献类型：
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作者：
Hasegawa K;Tanaka S;Fujiki F;Morimoto S;Nakano K;Kinoshita H;Okumura A;Fujioka Y;Urakawa R;Nakajima H;Tatsumi N;Nakata J;Takashima S;Nishida S;Tsuboi A;Oka Y;Oji Y;Miyoshi E;Hirata T;Kumanogoh A;Sugiyama H;Hosen N
为了改善癌症免疫治疗，重要的是要了解肿瘤细胞如何抵消免疫监视。在这项研究中，我们试图确定与白血病细胞对细胞毒性T细胞（CTL）介导的细胞溶解的抗性相关的细胞表面分子。为此，我们首先建立了数千种与MLL/AF 9小鼠白血病细胞反应的单克隆抗体（mAb）。这些单克隆抗体中只有两种，命名为R54和B2，优先结合白血病细胞耐肿瘤细胞抗原特异性CTL的细胞溶解。通过表达克隆将这些mAb识别的抗原鉴定为相同的蛋白质CD 43，尽管它们与造血细胞亚群的结合模式彼此之间以及与预先存在的泛CD 43 mAb S11之间存在显著差异。R54和B2的表位，而不是S11，是唾液酸酶敏感的，并在白血病细胞上以不同的水平表达，这表明R54或B2的结合与CD 43的糖基化状态相关。R54 high白血病细胞可能表达富含唾液酸的CD 43，对CTL介导的细胞溶解具有高度抗性。此外，白血病细胞中CD 43的丢失或白血病细胞的神经氨酸酶处理使白血病细胞对CTL介导的细胞裂解敏感。这些结果表明，富含唾液酸的CD 43，其含有多个赋予净负表面电荷的唾液酸残基，保护白血病细胞免受CTL介导的细胞裂解。此外，R54 high或B2 high白血病细胞在存在获得性免疫的情况下优先在体内存活。总之，这些结果表明，糖基化状态的CD 43白血病与敏感性CTL介导的细胞溶解在体外和体内。因此，调节CD 43糖基化是增强CTL介导的免疫治疗的潜在策略。
To improve cancer immunotherapy, it is important to understand how tumor cells counteract immune-surveillance. In this study, we sought to identify cell-surface molecules associated with resistance of leukemia cells to cytotoxic T cell (CTL)-mediated cytolysis. To this end, we first established thousands of monoclonal antibodies (mAbs) that react with MLL/AF9 mouse leukemia cells. Only two of these mAbs, designated R54 and B2, bound preferentially to leukemia cells resistant to cytolysis by a tumor cell antigen–specific CTLs. The antigens recognized by these mAbs were identified by expression cloning as the same protein, CD43, although their binding patterns to subsets of hematopoietic cells differed significantly from each other and from a pre-existing pan-CD43 mAb, S11. The epitopes of R54 and B2, but not S11, were sialidase-sensitive and expressed at various levels on leukemia cells, suggesting that binding of R54 or B2 is associated with the glycosylation status of CD43. R54high leukemia cells, which are likely to express sialic acid-rich CD43, were highly resistant to CTL-mediated cytolysis. In addition, loss of CD43 in leukemia cells or neuraminidase treatment of leukemia cells sensitized leukemia cells to CTL-mediated cell lysis. These results suggest that sialic acid-rich CD43, which harbors multiple sialic acid residues that impart a net negative surface charge, protects leukemia cells from CTL-mediated cell lysis. Furthermore, R54high or B2high leukemia cells preferentially survived in vivo in the presence of adaptive immunity. Taken together, these results suggest that the glycosylation status of CD43 on leukemia is associated with sensitivity to CTL-mediated cytolysis in vitro and in vivo. Thus, regulation of CD43 glycosylation is a potential strategy for enhancing CTL-mediated immunotherapy.