Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Japan.
Front Immunol. 2020 Oct 20;11:581301. doi: 10.3389/fimmu.2020.581301. eCollection 2020.
Murine and human invariant natural killer T (iNKT) lymphocytes are activated by α-galactosylceramide (α-GalCer) presented on CD1d. α-GalCer was first described as a lipid that had strong anti-metastatic effects in a mouse melanoma model, and it has subsequently been shown to induce efficient iNKT cell dependent tumor immunity in several tumor models. We have shown that α-GalCer treatment leads to a weak reduction of polyp burden in the autochthonous mouse model for human colon cancer, however this treatment resulted in upregulation of the inhibitory receptor PD-1 on iNKT cells. While anti-PD-1 treatment can prevent immune-suppression in other cancer types, human colon cancer is generally resistant to this treatment. Here we have used the model to investigate whether a combined treatment with α-GalCer and PD-1 blockade results in improved effects on polyp development. We find that PD-1 expression was high on T cells in polyps and lamina propria (LP) of mice compared to polyp free littermates. Anti-PD-1 treatment alone promoted Tbet expression in iNKT cells and CD4 T cells, but did not significantly reduce polyp numbers. However, the combined treatment with anti-PD-1 and α-GalCer had synergistic effects, resulting in highly significant reduction of polyp numbers in the small and large intestine. Addition of PD-1 blockade to α-GalCer treatment prevented loss of iNKT cells that were skewed towards a TH1-like iNKT1 phenotype specifically in polyps. It also resulted in TH1 skewing and increased granzyme B expression of CD4 T cells. Taken together this demonstrates that a combination of immune stimulation targeting iNKT cells and checkpoint blockade may be a promising approach to develop for improved tumor immunotherapy.
鼠和人天然不变的自然杀伤 T(iNKT)细胞被 CD1d 上呈现的α-半乳糖神经酰胺(α-GalCer)激活。α-GalCer 最初被描述为一种在鼠黑色素瘤模型中具有强烈抗转移作用的脂质，随后在几种肿瘤模型中显示可诱导有效的 iNKT 细胞依赖的肿瘤免疫。我们已经表明，α-GalCer 处理导致在同源的人结肠癌小鼠模型中息肉负担的轻微减少，然而，这种处理导致 iNKT 细胞上抑制性受体 PD-1 的上调。虽然抗 PD-1 治疗可以防止其他癌症类型的免疫抑制，但人类结肠癌通常对这种治疗有抵抗力。在这里，我们使用该模型来研究 α-GalCer 和 PD-1 阻断的联合治疗是否对息肉发育有改善作用。我们发现，与无息肉的同窝仔相比，PD-1 在 小鼠的息肉和粘膜固有层(LP)中的 T 细胞上表达较高。单独使用抗 PD-1 治疗促进了 iNKT 细胞和 CD4 T 细胞中的 Tbet 表达，但不能显著减少息肉数量。然而，抗 PD-1 和 α-GalCer 的联合治疗具有协同作用，导致小肠和大肠中的息肉数量显著减少。在 α-GalCer 治疗中添加 PD-1 阻断可防止 iNKT 细胞的丢失，这些细胞偏向于特定于息肉的 TH1 样 iNKT1 表型。它还导致 TH1 偏向和 CD4 T 细胞中颗粒酶 B 表达的增加。总之，这表明针对 iNKT 细胞的免疫刺激和检查点阻断的联合可能是开发改善肿瘤免疫治疗的有前途的方法。
