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Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido.
- Source :
-
Nature medicine [Nat Med] 2011 Aug 28; Vol. 17 (9), pp. 1094-100. Date of Electronic Publication: 2011 Aug 28. - Publication Year :
- 2011
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1546-170X
- Volume :
- 17
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Nature medicine
- Publication Type :
- Academic Journal
- Accession number :
- 21873989
- Full Text :
- https://doi.org/10.1038/nm.2438