KrasG12D mutation contributes to regulatory T cell conversion through activation of the MEK/ERK pathway in pancreatic cancer. (1st April 2019)

• Record Type: Journal Article
• Authors: Cheng, He; Fan, Kun; Luo, Guopei; Fan, Zhiyao; Yang, Chao; Huang, Qiuyi; Jin, Kaizhou; Xu, Jin; Yu, Xianjun; Liu, Chen
• Is Part Of: Cancer letters. Volume 446(2019)
• Page Start: 103
• Page End: 111
• Publication Date: 2019-04-01
• Subjects: Pancreatic cancer -- Immunosuppressive -- KrasG12D mutation -- IL-10 -- TGF-β; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.01.013
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Genetic alterations have been attributed to the abnormal immune microenvironment in cancer. However, the relationship between the Kras G12D mutation and regulatory T cells (Tregs) in pancreatic cancer remains unclear. In this study, we found that Kras G12D 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 G12D mutation were associated with higher levels of Tregs, and knockout of the Kras G12D mutation reversed this effect. In addition, overexpression of the Kras G12D mutation in wild-type Kras tumour cells resulted in conversion of CD4 + CD25 − T cells into Tregs. We also found that in tumour cells, the Kras G12D 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 G12D 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. Highlights: The Kras G12D mutation status and tumour-infiltrating Tregs in pancreatic cancer tissues were significantly correlated in local microenvironment.. IL-10 and TGF-β are critical factors, which involved in the regulation of Kras G12D mutation contributes to regulatory T cell conversion in pancreatic cancer. Our study identified that genetic alteration attributed to the abnormal immune microenvironment in pancreatic cancer.