Journal
NATURE MEDICINE
Volume 17, Issue 9, Pages 1094-U99Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2438
Keywords
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Funding
- US National Institutes of Health (NIH) [R01 CA102613]
- Geoffrey Beene Cancer Research Center
- Dutch GIST Foundation
- GIST
- Society for University
- NIH [R01 CA102774, R01 HL55748, P50 CA140146, R24 CA83084, P30 CA08748]
- LifeRaft Group and Starr Cancer Consortium
- Cancer Center [NCI P30-CA008748]
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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.
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