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KrasG12D mutation contributes to regulatory T cell conversion through activation of the MEK/ERK pathway in pancreatic cancer
- Source :
- Cancer Letters. 446:103-111
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Cancer Research
Regulatory T cell
chemical and pharmacologic phenomena
Gene mutation
Biology
medicine.disease
medicine.disease_cause
03 medical and health sciences
Interleukin 10
030104 developmental biology
0302 clinical medicine
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Pancreatic cancer
Cancer research
medicine
KRAS
Infiltration (medical)
Transforming growth factor
Subjects
Details
- ISSN :
- 03043835
- Volume :
- 446
- Database :
- OpenAIRE
- Journal :
- Cancer Letters
- Accession number :
- edsair.doi...........215ee5689185b859c56401652f741253