Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China.
Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China.
Cancer Lett. 2019 Apr 1;446:103-111. doi: 10.1016/j.canlet.2019.01.013. Epub 2019 Jan 18.
Genetic alterations have been attributed to the abnormal immune microenvironment in cancer. However, the relationship between the Kras mutation and regulatory T cells (Tregs) in pancreatic cancer remains unclear. In this study, we found that Kras mutation status as determined by ddPCR correlated with high levels of Treg infiltration in resectable pancreatic cancer tissues. Compared to wild-type tumour cells, tumours cells with the Kras mutation were associated with higher levels of Tregs, and knockout of the Kras mutation reversed this effect. In addition, overexpression of the Kras mutation in wild-type Kras tumour cells resulted in conversion of CD4CD25 T cells into Tregs. We also found that in tumour cells, the Kras mutation activated the MEK/ERK pathway, thereby up-regulating the levels of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which induced Treg conversion. In summary, Kras mutation plays a critical role in Treg conversion and contributes to an immunosuppressive tumour microenvironment in pancreatic cancer. These results provide new insights into the relationship between gene mutation and immune escape.
遗传改变归因于癌症中异常的免疫微环境。然而，Kras 突变与胰腺癌中的调节性 T 细胞（Tregs）之间的关系尚不清楚。在这项研究中，我们发现，ddPCR 确定的 Kras 突变状态与可切除胰腺癌组织中 Treg 浸润水平升高相关。与野生型肿瘤细胞相比，具有 Kras 突变的肿瘤细胞与更高水平的 Tregs 相关，并且敲除 Kras 突变逆转了这种效应。此外，在野生型 Kras 肿瘤细胞中过表达 Kras 突变导致 CD4CD25 T 细胞转化为 Tregs。我们还发现，在肿瘤细胞中，Kras 突变激活了 MEK/ERK 通路，从而上调白细胞介素 10（IL-10）和转化生长因子-β（TGF-β）的水平，诱导 Treg 转化。总之，Kras 突变在 Treg 转化中起关键作用，并导致胰腺癌中免疫抑制性肿瘤微环境。这些结果为基因突变与免疫逃逸之间的关系提供了新的见解。
