Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido Journal Article
| Authors: | Balachandran, V. P.; Cavnar, M. J.; Zeng, S.; Bamboat, Z. M.; Ocuin, L. M.; Obaid, H.; Sorenson, E. C.; Popow, R.; Ariyan, C.; Rossi, F.; Besmer, P.; Guo, T.; Antonescu, C. R.; Taguchi, T.; Yuan, J.; Wolchok, J. D.; Allison, J. P.; DeMatteo, R. P. |
| Article Title: | Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido |
| 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. © 2011 Nature America, Inc. All rights reserved. |
| Keywords: | controlled study; protein expression; unclassified drug; nonhuman; flow cytometry; cd8+ t lymphocyte; cd8-positive t-lymphocytes; animal cell; mouse; animals; mice; gastrointestinal stromal tumor; imatinib; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; cytotoxic t lymphocyte antigen 4 antibody; apoptosis; enzyme inhibition; animal experiment; animal model; pyrimidines; mice, inbred c57bl; blotting, western; gene expression regulation, neoplastic; regulatory t lymphocyte; immunotherapy; drug mechanism; t-lymphocytes, regulatory; reverse transcriptase polymerase chain reaction; microarray analysis; chromatin immunoprecipitation; down regulation; piperazines; indoleamine 2,3 dioxygenase; indoleamine-pyrrole 2,3,-dioxygenase; drug sensitivity; tryptophan; 1 methyl dextro tryptophan; 9d9 antibody; 9h10 antibody |
| Journal Title: | Nature Medicine |
| Volume: | 17 |
| Issue: | 9 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2011-08-28 |
| Start Page: | 1094 |
| End Page: | 1100 |
| Language: | English |
| DOI: | 10.1038/nm.2438 |
| PROVIDER: | scopus |
| PUBMED: | 21873989 |
| PMCID: | PMC3278279 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 3 October 2011" - "CODEN: NAMEF" - "Source: Scopus" |
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