Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.
Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, 157-8535, Japan.
Biochem Biophys Res Commun. 2019 Oct 15;518(2):331-336. doi: 10.1016/j.bbrc.2019.08.058. Epub 2019 Aug 14.
Interleukin-33 (IL-33) is a nuclear-associated cytokine of the IL-1 family. IL-33 and its receptor ST2 axis exert conflicting anti-tumor and pro-tumor effects in various tumors. In this study, we examined the role of endogenously produced IL-33 in the colon-26 tumor model, in which involvement of the IL-33:ST2 pathway was negligible on the tumor side. We found that the generation of regulatory T cells (Tregs) and CD8 T cells, and IFN-γ expression by both CD4 and CD8 T cells (T cell activation) were impaired in IL-33-deficient mice. Overall antitumor responses, assessed by tumor growth and IFN-γ expression by tumor-infiltrating CD8 T cells, were also impaired, even after Treg adjustment prior to tumor inoculation. These results indicate that endogenous IL-33 augmented CD8 T cell-mediated antitumor responses in this colon carcinoma model, with higher CD8 T cell-infiltration and overcoming pro-tumor effects by increased Tregs. Exogenous application of IL-33 into the tumors did not enhance CD8 T cell-mediated antitumor responses despite marked elevation of innate responses showing upregulation of proinflammatory cytokine/chemokine expression, neutrophil recruitment, and dendritic cell activation. Our results suggest a dual role for endogenous IL-33 in antitumor responses and suggest that the balance of CD8 T cells:Tregs in the tumor microenvironment is one of key factors for estimating the contribution of IL-33-mediated antitumor responses. Therefore, the development of IL-33-based cancer immunotherapy may require a target cell-specific approach.
白细胞介素 33 (IL-33) 是白细胞介素 1 家族的一种核相关细胞因子。IL-33 及其受体 ST2 轴在各种肿瘤中发挥着相互矛盾的抗肿瘤和促肿瘤作用。在这项研究中，我们研究了内源性产生的 IL-33 在结肠-26 肿瘤模型中的作用，其中 IL-33:ST2 途径在肿瘤侧的参与可以忽略不计。我们发现，调节性 T 细胞 (Treg) 和 CD8 T 细胞的产生，以及 CD4 和 CD8 T 细胞的 IFN-γ 表达 (T 细胞活化) 在 IL-33 缺陷小鼠中受损。即使在肿瘤接种前调整 Treg 后，整体抗肿瘤反应，通过肿瘤浸润性 CD8 T 细胞的肿瘤生长和 IFN-γ 表达来评估，也受到损害。这些结果表明，内源性 IL-33 增强了这种结肠腺癌模型中 CD8 T 细胞介导的抗肿瘤反应，CD8 T 细胞浸润增加，并通过增加 Treg 克服促肿瘤作用。尽管先天反应明显升高，表现为促炎细胞因子/趋化因子表达上调、中性粒细胞募集和树突状细胞激活，但外源性应用 IL-33 到肿瘤中并没有增强 CD8 T 细胞介导的抗肿瘤反应。我们的结果表明内源性 IL-33 在抗肿瘤反应中具有双重作用，并表明肿瘤微环境中 CD8 T 细胞：Treg 的平衡是估计 IL-33 介导的抗肿瘤反应贡献的关键因素之一。因此，基于 IL-33 的癌症免疫疗法的发展可能需要针对特定靶细胞的方法。
