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

Vinod P. Balachandran, Michael J. Cavnar, Shan Zeng, Zubin M. Bamboat, Lee M. Ocuin, Hebroon Obaid, Eric C. Sorenson, Rachel Popow, Charlotte Ariyan, Ferdinand Rossi, Peter Besmer, Tianhua Guo, Cristina R. Antonescu, Takahiro Taguchi, Jianda Yuan, Jedd D. Wolchok, James P. Allison, Ronald P. Dematteo

Research output: Contribution to journalArticlepeer-review

449 Scopus citations

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.

Original languageEnglish
Pages (from-to)1094-1100
Number of pages7
JournalNature Medicine
Volume17
Issue number9
DOIs
StatePublished - Sep 2011

Bibliographical note

Funding Information:
discussions, and M. Gonen for statistical assistance. This work was supported by US National Institutes of Health (NIH) grant R01 CA102613, the Geoffrey Beene Cancer Research Center, Mr. J.H.L. Pit and Mrs. Pit-van Karnebeek and the Dutch GIST Foundation, GIST Cancer Research Fund and Swim Across America (R.P.D.); the Society for University Surgeons Ethicon Research Fellowship Award (V.P.B.); and NIH grants R01 CA102774, R01 HL55748 and P50 CA140146, LifeRaft Group and Starr Cancer Consortium (P.B.). Technical services provided by the Animal Imaging Core Facility were supported by the Small-Animal Imaging Research Program (SAIRP) NIH grants R24 CA83084 and P30 CA08748; the Molecular Cytology Core Facility was supported by Cancer Center Support grant NCI P30-CA008748.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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