Vaccine Branch and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
Cancer Res. 2013 Mar 1;73(5):1514-23. doi: 10.1158/0008-5472.CAN-12-2567. Epub 2013 Jan 14.
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.
目前，人们并不了解在任何给定的肿瘤中占主导地位的调节性细胞类型的性质。在这里，我们针对结直肠癌和肾癌的同种异体模型中的调节性 T 细胞（Treg）和 II 型自然杀伤 T（NKT）细胞回答了这个问题。在具有 I 型和 II 型 NKT 细胞的小鼠中，或在既没有 I 型也没有 II 型 NKT 细胞的小鼠中，Treg 耗竭足以防止肿瘤生长。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 成为主要的抑制物，而在缺乏 I 型 NKT 细胞的小鼠中，未被抑制的 II 型 NKT 细胞即使阻断 Tregs 也可以抑制肿瘤免疫。我们通过三种方式证实了这一假设，即通过重新构建 I 型 NKT 细胞，以及分别用抗体或激动剂硫酸酯选择性阻断或激活 II 型 NKT 细胞。通过这种方式，我们表明阻断 II 型 NKT 细胞和 Treg 两者对于消除肿瘤免疫抑制是必要的，但是第三种细胞，即 I 型 NKT 细胞，决定了这些调节机制之间的平衡。由于癌症患者通常具有缺陷的 I 型 NKT 细胞功能，因此管理这三种 T 细胞亚群之间的这种微妙平衡可能对于人类癌症免疫疗法的成功至关重要。
