Delicate Balance among Three Types of T Cells in Concurrent Regulation of Tumor Immunity
Delicate Balance among Three Types of T Cells in Concurrent Regulation of Tumor Immunity
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DOI：
10.1158/0008-5472.can-12-2567
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发表时间：
2013-03-01
期刊：
影响因子：
11.2
通讯作者：
Terabe, Masaki
中科院分区：
文献类型：
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作者：
Izhak, Liat;Ambrosino, Elena;Terabe, Masaki
目前尚不清楚在任何给定肿瘤中占主导地位的调节细胞类型的性质。在这里，我们针对结直肠癌和肾癌同基因模型中的调节性 T 细胞 (Treg) 和 II 型自然杀伤 T (NKT) 细胞解决了这个问题。在同时具有 I 型和 II 型 NKT 细胞的小鼠中，或在两种类型的 NKT 细胞都没有的小鼠中，Treg 的消除足以防止肿瘤生长。令人惊讶的是，在仅缺乏 I 型 NKT 细胞的小鼠中，Treg 阻断不足以提供保护。因此，我们假设 II 型 NKT 细胞可能被 I 型 NKT 细胞中和，使 Tregs 成为主要抑制因子，而在缺乏 I 型 NKT 细胞的小鼠中，即使当 Tregs 被阻断时，不受对抗的 II 型 NKT 细胞也可以抑制肿瘤免疫。我们通过重建 I 型 NKT 细胞以及分别用抗体或激动剂硫苷脂选择性阻断或激活 II 型 NKT 细胞，以 3 种方式证实了这一假设。通过这种方式，我们表明，阻断 II 型 NKT 细胞和 Tregs 是消除肿瘤免疫抑制所必需的，但第三种细胞，即 I 型 NKT 细胞，决定了这些调节机制之间的平衡。由于癌症患者通常存在 I 型 NKT 细胞功能缺陷，因此管理 3 个 T 细胞亚群之间的这种微妙平衡可能对于人类癌症免疫治疗的成功至关重要。癌症研究； 73（5）； 1514-23。 (C) 2012 年 AACR。
The nature of the regulatory cell types that dominate in any given tumor is not understood at present. Here, we addressed this question for regulatory T cells (Treg) and type II natural killer T (NKT) cells in syngeneic models of colorectal and renal cancer. In mice with both type I and II NKT cells, or in mice with neither type of NKT cell, Treg depletion was sufficient to protect against tumor outgrowth. Surprisingly, in mice lacking only type I NKT cells, Treg blockade was insufficient for protection. Thus, we hypothesized that type II NKT cells may be neutralized by type I NKT cells, leaving Tregs as the primary suppressor, whereas in mice lacking type I NKT cells, unopposed type II NKT cells could suppress tumor immunity even when Tregs were blocked. We confirmed this hypothesis in 3 ways by reconstituting type I NKT cells as well as selectively blocking or activating type II NKT cells with antibody or the agonist sulfatide, respectively. In this manner, we showed that blockade of both type II NKT cells and Tregs is necessary to abrogate suppression of tumor immunity, but a third cell, the type I NKT cell, determines the balance between these regulatory mechanisms. As patients with cancer often have deficient type I NKT cell function, managing this delicate balance among 3 T-cell subsets may be critical for the success of immunotherapy for human cancer. Cancer Res; 73(5); 1514-23. (C) 2012 AACR.