1. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.
- Author
-
Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, Sorenson EC, Popow R, Ariyan C, Rossi F, Besmer P, Guo T, Antonescu CR, Taguchi T, Yuan J, Wolchok JD, Allison JP, and DeMatteo RP
- Subjects
- Animals, Benzamides, Blotting, Western, CD8-Positive T-Lymphocytes drug effects, Chromatin Immunoprecipitation, Flow Cytometry, Gastrointestinal Stromal Tumors drug therapy, Gastrointestinal Stromal Tumors therapy, Gene Expression Regulation, Neoplastic physiology, Humans, Imatinib Mesylate, Mice, Mice, Inbred C57BL, Microarray Analysis, Piperazines therapeutic use, Proto-Oncogene Proteins c-kit metabolism, Pyrimidines therapeutic use, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocytes, Regulatory drug effects, CD8-Positive T-Lymphocytes immunology, Gastrointestinal Stromal Tumors immunology, Gene Expression Regulation, Neoplastic drug effects, Immunotherapy methods, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Piperazines pharmacology, Pyrimidines pharmacology, T-Lymphocytes, Regulatory immunology
- 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.
- Published
- 2011
- Full Text
- View/download PDF