Gutting Tobias, Weber Christian A, Weidner Philip, Herweck Frank, Henn Sarah, Friedrich Teresa, Yin Shuiping, Kzhyshkowska Julia, Gaiser Timo, Janssen Klaus-Peter, Reindl Wolfgang, Ebert Matthias P A, Burgermeister Elke
Dept. of Medicine II, University Hospital Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Dept. of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Oncoimmunology. 2018 Feb 1;7(5):e1423168. doi: 10.1080/2162402X.2017.1423168. eCollection 2018.
To identify novel hubs for cancer immunotherapy, we generated J mice with concomitant deletion of the drugable transcription factor PPARγ and transgenic overexpression of the mutant oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant mice with the PPARγ-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPARγ in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation.
为了确定癌症免疫治疗的新关键靶点，我们构建了J小鼠，其肠细胞中可药物化的转录因子PPARγ同时缺失且突变癌基因转基因过表达。动物出现上皮增生、透壁性炎症以及小肠锯齿状腺瘤，CD3+FOXP3+T细胞和巨噬细胞浸润至非恶性黏膜的固有层。在锯齿状息肉内，CD3+CD8+T细胞和磷酸化ERK1/2减少，衰老标志物P21和巨噬细胞数量上调，表明存在免疫抑制性组织微环境。用PPARγ激动剂罗格列酮治疗突变小鼠可增加M1巨噬细胞数量，降低IL4表达并减少小鼠息肉负荷。罗格列酮还促进人THP1来源巨噬细胞的M1极化，并降低分离的小鼠淋巴细胞中的mRNA。因此，PPARγ在上皮细胞和免疫细胞区室中对致癌驱动因子突变RAS的抑制作用可能是预防或治疗与肠道炎症相关的人类恶性肿瘤的未来靶点。
