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

被引：63

作者：

Chen, He ^{[1
,2
,3
]}

Fan, Kun ^{[1
,2
,3
]}

Luo, Guopei ^{[1
,2
,3
]}

Fan, Zhiyao ^{[1
,2
,3
]}

Yang, Chao ^{[1
,2
,3
]}

Huang, Qiuyi ^{[1
,2
,3
]}

Jin, Kaizhou ^{[1
,2
,3
]}

Xu, Jin ^{[1
,2
,3
]}

Yu, Xianjun ^{[1
,2
,3
]}

Liu, Chen ^{[1
,2
,3
]}

机构：

[1] Fudan Univ, Shanghai Canc Ctr, Dept Pancreat Surg, 270 DongAn Rd, Shanghai 200032, Peoples R China

[2] Fudan Univ, Dept Oncol, Shanghai Med Coll, Shanghai, Peoples R China

[3] Shanghai Pancreat Canc Inst, Shanghai, Peoples R China

来源：

CANCER LETTERS | 2019年 / 446卷

基金：

中国国家自然科学基金;

关键词：

Pancreatic cancer; Immunosuppressive; Kras(G12D) mutation; IL-10; TGF-beta; ONCOGENIC KRAS; VACCINATION; PROGNOSIS; PEPTIDES; SUBTYPES;

D O I：

10.1016/j.canlet.2019.01.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 ICrasG1213 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 ICrasG12D mutation activated the MEK/ERK pathway, thereby up-regulating the levels of interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta), 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.

引用

页码：103 / 111

页数：9

共 29 条

[1] Generation of stable CD4+ and CD8+ T cell lines from patients immunized with ras oncogene-derived peptides reflecting codon 12 mutations [J].