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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 (Treg 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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Figure 1: CD8+ T cells contribute to antitumor effects of imatinib.
Figure 2: Imatinib induces Treg apoptosis selectively within the tumor.
Figure 3: Imatinib alters intratumoral T cells through inhibition of Ido.
Figure 4: Imatinib reduces IDO expression through inhibition of oncogenic KIT signaling.
Figure 5: Ratio of intratumoral CD8+ T cells to Treg cells correlates with imatinib sensitivity in human GIST.
Figure 6: CTLA-4 blockade is synergistic with imatinib.

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Acknowledgements

We thank members of the Genomics, Tissue Procurement, Monoclonal Antibody, Molecular Cytology and Animal Imaging core facilities and the Laboratory of Comparative Pathology of Sloan-Kettering Institute. We acknowledge H.F. Gallardo, Y. Li, B. Zaidi, T. Rasalan, R. Chua, the Research Animal Resource Center, members of the laboratories of B. Singh and M. Weiser, and R. Holmes for technical assistance and logistical support, G. Rizzuto, D. Hirschhorn-Cymerman, D. Schaer, F. Avogadri and T. Merghoub for helpful 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.

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All authors contributed to experimental design. V.P.B., M.J.C., S.Z., Z.M.B., H.O., R.P., C.A., T.G., C.R.A. and J.Y. performed the experiments. All authors assisted in data analysis. V.P.B. and R.P.D. wrote and prepared the manuscript with critical comments from all authors.

Corresponding author

Correspondence to Ronald P DeMatteo.

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Competing interests

R.P.D. serves as a consultant for Novartis and has received honoraria. P.B. has received a commercial research grant from Novartis. J.D.W. serves as a consultant to Novartis and Bristol-Meyers Squibb. CTLA-4 blocking antibody is currently in clinical development by Medarex and Bristol-Meyers Squibb. J.P.A. is a consultant for Medarex and Bristol-Meyers Squibb and is an inventor of intellectual property that has been licensed to Medarex and Bristol-Meyers Squibb by the University of California–Berkeley.

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Balachandran, V., Cavnar, M., Zeng, S. et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med 17, 1094–1100 (2011). https://doi.org/10.1038/nm.2438

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