在转移过程中,癌细胞侵入,玻璃体腔内,进入流通,外渗,定殖目标器官。这里,我们研究了白细胞介素(IL)-22在转移中的作用。免疫细胞来源的IL-22作用于上皮组织,促进组织损伤后的再生和愈合,但它也与恶性肿瘤有关。IL-22缺陷的小鼠和用IL-22抗体治疗的小鼠被保护免受结肠癌衍生的肝和肺转移形成,而IL-22的过表达促进了转移。机械上,IL-22作用于内皮细胞,通过诱导内皮氨肽酶N促进内皮通透性和癌细胞迁移。多参数流式细胞术和对癌细胞外渗到肝脏中的免疫细胞进行单细胞测序显示iNKT17细胞是IL-22的来源。iNKT细胞缺陷小鼠表现出减少的转移,通过注射野生型逆转,但不是缺乏Il22,不变的自然杀伤T(iNKT)细胞。产生IL-22的iNKT细胞促进转移的组织驻留,正如共生所证明的。因此,IL-22可能是预防转移的治疗靶标。
During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.