Center for Cancer Immunology and Cutaneous Biology Research Center, Department of Dermatology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110.
Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2646-2651. doi: 10.1073/pnas.1815016116. Epub 2019 Jan 29.
Chronic inflammation's tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls ( = 0.0002). IL-33's direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33-Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model ( < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.
慢性炎症的促肿瘤作用已得到广泛认可；然而，这种免疫环境发展的机制尚不清楚。研究从急性、肿瘤抑制到慢性、促肿瘤变应性接触性皮炎（ACD）的转变，揭示了促肿瘤慢性炎症的发展机制。表皮衍生的白细胞介素（IL）-33 的上调及其在皮肤中诱导调节性 T 细胞（Treg）的积累先于急性向慢性 ACD 的转变，并引发慢性 ACD 中的促肿瘤免疫环境。与野生型对照相比，缺乏 IL-33 的小鼠免受慢性 ACD 及其皮肤癌后遗症的影响（=0.0002）。IL-33 对 Treg 的直接信号传导是皮肤中促肿瘤免疫环境发展所必需的。IL-33-Treg 信号传导对于结肠炎模型中的慢性结肠炎及其相关结直肠癌的发展也是必需的（<0.0001）。在易患慢性炎症性疾病的患者中，病变周围皮肤和结肠中明显增加的 IL-33 和 Treg 标志着这些部位。我们的研究结果阐明了 IL-33/Treg 轴在慢性炎症性疾病中创建促肿瘤免疫环境中的作用，并为高危患者的癌症预防和治疗提供了治疗靶点。
