KrasG12D mutation contributes to regulatory T cell conversion through activation of the MEK/ERK pathway in pancreatic cancer.

Genetic alterations have been attributed to the abnormal immune microenvironment in cancer. However, the relationship between the KrasG12D mutation and regulatory T cells (Tregs) in pancreatic cancer remains unclear. In this study, we found that KrasG12D 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 KrasG12D mutation were associated with higher levels of Tregs, and knockout of the KrasG12D mutation reversed this effect. In addition, overexpression of the KrasG12D 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 KrasG12D 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, KrasG12D 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.