Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido

被引：427

作者：

Balachandran, Vinod P. ^{[1
]}

Cavnar, Michael J. ^{[1
]}

Zeng, Shan ^{[1
]}

Bamboat, Zubin M. ^{[1
]}

Ocuin, Lee M. ^{[1
]}

Obaid, Hebroon ^{[1
]}

Sorenson, Eric C. ^{[1
]}

Popow, Rachel ^{[1
]}

Ariyan, Charlotte ^{[1
]}

Rossi, Ferdinand ^{[2
]}

Besmer, Peter ^{[2
]}

Guo, Tianhua ^{[3
]}

Antonescu, Cristina R. ^{[3
]}

Taguchi, Takahiro ^{[4
]}

Yuan, Jianda ^{[5
]}

Wolchok, Jedd D. ^{[5
,6
]}

Allison, James P. ^{[5
,7
]}

DeMatteo, Ronald P. ^{[1
]}

机构：

[1] Mem Hosp, Dept Surg, New York, NY USA

[2] Sloan Kettering Inst, Dev Biol Program, New York, NY USA

[3] Mem Hosp, Dept Pathol, New York, NY USA

[4] Kochi Univ, Div Human Hlth & Med Sci, Grad Sch Kuroshio Sci, Kochi 780, Japan

[5] Ludwig Ctr Canc Immunotherapy, New York, NY USA

[6] Mem Hosp, Dept Med, New York, NY USA

[7] Sloan Kettering Inst, Program Immunol, New York, NY USA

来源：

NATURE MEDICINE | 2011年 / 17卷 / 09期

基金：

美国国家卫生研究院;

关键词：

INDOLEAMINE 2,3-DIOXYGENASE EXPRESSION; RECEPTOR TYROSINE KINASE; DENDRITIC CELLS; MOUSE MODEL; COMBINATION IMMUNOTHERAPY; TRYPTOPHAN CATABOLISM; CTLA-4; BLOCKADE; OVARIAN-CANCER; REGULATORY CELLS; C-KIT;

D O I：

10.1038/nm.2438

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T-reg cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.

引用

页码：1094 / U99

页数：8

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