Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido |
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Authors: | Balachandran Vinod P Cavnar Michael J Zeng Shan Bamboat Zubin M Ocuin Lee M Obaid Hebroon Sorenson Eric C Popow Rachel Ariyan Charlotte Rossi Ferdinand Besmer Peter Guo Tianhua Antonescu Cristina R Taguchi Takahiro Yuan Jianda Wolchok Jedd D Allison James P DeMatteo Ronald P |
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Institution: | Department of Surgery, Memorial Hospital, New York, New York, USA. |
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Abstract: | 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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