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

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Abstract
Imatinib has been proposed as a therapy for gastrointestinal stromal tumors, owing to its side effects on KIT, a kinase often mutated in this type of tumor. This report shows that a key aspect of imatinib's effect is its modulation of antitumor immune responses by a mechanism regulating Ido expression. Combining imatinib with CTLA-4 blockade emerges as a potential efficacious therapeutic approach for gastrointestinal stromal tumors. 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 (Treg 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.