Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, United States.
Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, United States.
Front Immunol. 2022 Aug 15;13:932412. doi: 10.3389/fimmu.2022.932412. eCollection 2022.
Immune cells and the cytokines they produce are important mediators of the transition from colitis to colon cancer, but the mechanisms mediating this disease progression are poorly understood. Interferon gamma (IFN-γ) is known to contribute to the pathogenesis of colitis through immune modulatory mechanisms, and through direct effects on endothelial and epithelial homeostasis. Here we explore whether IFN-γ influences tumor progression by expanding the effector memory T cells (T) population and restricting the expression of tumor suppressors in a preclinical model of spontaneous colitis-associated colorectal cancer (CAC). We show that IFN-γ expression is significantly increased both in the T cells and the colonic mucosal epithelia of mice with a T cell-restricted deletion of the TGF-β intermediate, SMAD4 (Smad4). The increase of IFN-γ expression correlates with the onset of spontaneous CAC in Smad4 mice by 6 months of age. This phenotype is greatly ameliorated by the introduction of a germline deletion of IFN-γ in Smad4 mice (Smad4/IFN-γ, DKO). DKO mice had a significantly reduced incidence and progression of CAC, and a decrease in the number of mucosal CD4 T cells, when compared to those of Smad4 mice. Similarly, the colon epithelia of DKO mice exhibited a non-oncogenic signature with a decrease in the expression of iNOS and p-STAT1, and a restoration of the tumor suppressor gene, 15-hydroxyprostaglandin dehydrogenase (15-PGDH). , treatment of human colon cancer cells with IFN-γ decreased the expression of 15-PGDH. Our data suggest that Smad4-deficient T cells promote CAC through mechanisms that include an IFN-γ-dependent suppression of the tumor suppressor 15-PGDH.
免疫细胞及其产生的细胞因子是从结肠炎向结肠癌转化的重要介质，但介导这种疾病进展的机制尚不清楚。干扰素 γ（IFN-γ）通过免疫调节机制以及对内皮和上皮稳态的直接影响，已知有助于结肠炎的发病机制。在这里，我们探索了 IFN-γ 是否通过扩展效应记忆 T 细胞（T）群体并限制肿瘤抑制因子在自发性结肠炎相关结直肠癌（CAC）的临床前模型中的表达来影响肿瘤进展。我们表明，在 TGF-β 中间 SMAD4（Smad4）T 细胞受限缺失的小鼠的 T 细胞和结肠黏膜上皮中，IFN-γ 的表达均显著增加。IFN-γ 表达的增加与 Smad4 小鼠自发 CAC 的发生相关，其在 6 个月龄时出现。这种表型通过在 Smad4 小鼠中引入 IFN-γ 的种系缺失（Smad4/IFN-γ，DKO）得到极大改善。与 Smad4 小鼠相比，DKO 小鼠的 CAC 发生率和进展明显降低，并且黏膜 CD4 T 细胞数量减少。同样，DKO 小鼠的结肠上皮表现出非致癌特征，即 iNOS 和 p-STAT1 的表达减少，肿瘤抑制基因 15-羟基前列腺素脱氢酶（15-PGDH）的表达恢复。此外，IFN-γ 处理人结肠癌细胞会降低 15-PGDH 的表达。我们的数据表明，Smad4 缺陷 T 细胞通过包括 IFN-γ 依赖性抑制肿瘤抑制基因 15-PGDH 的机制促进 CAC。
