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

doi:10.1038/nm.2438

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

Surgery

Research output: Contribution to journal › Article › peer-review

465 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 language	English
Pages (from-to)	1094-1100
Number of pages	7
Journal	Nature Medicine
Volume	17
Issue number	9
DOIs	https://doi.org/10.1038/nm.2438
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.2438

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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. (2011). Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nature Medicine, 17(9), 1094-1100. https://doi.org/10.1038/nm.2438

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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.",

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

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.",

year = "2011",

month = sep,

doi = "10.1038/nm.2438",

language = "English",

volume = "17",

pages = "1094--1100",

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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 & Dematteo, RP 2011, 'Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido', Nature Medicine, vol. 17, no. 9, pp. 1094-1100. https://doi.org/10.1038/nm.2438

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AU - Balachandran, Vinod P.

AU - Cavnar, Michael J.

AU - Zeng, Shan

AU - Bamboat, Zubin M.

AU - Ocuin, Lee M.

AU - Obaid, Hebroon

AU - Sorenson, Eric C.

AU - Popow, Rachel

AU - Ariyan, Charlotte

AU - Rossi, Ferdinand

AU - Besmer, Peter

AU - Guo, Tianhua

AU - Antonescu, Cristina R.

AU - Taguchi, Takahiro

AU - Yuan, Jianda

AU - Wolchok, Jedd D.

AU - Allison, James P.

AU - Dematteo, Ronald P.

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PY - 2011/9

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N2 - 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.

AB - 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.

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ER -

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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