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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Rubin, B.P., Heinrich, M.C. & Corless, C.L. Gastrointestinal stromal tumour. Lancet 369, 1731–1741 (2007).
Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).
Heinrich, M.C. et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299, 708–710 (2003).
Demetri, G.D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).
Blanke, C.D. et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J. Clin. Oncol. 26, 626–632 (2008).
Cameron, S. et al. Immune cells in primary gastrointestinal stromal tumors. Eur. J. Gastroenterol. Hepatol. 20, 327–334 (2008).
van Dongen, M. et al. Anti-inflammatory M2 type macrophages characterize metastasized and tyrosine kinase inhibitor-treated gastrointestinal stromal tumors. Int. J. Cancer 127, 899–909 (2010).
Ménard, C. et al. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 69, 3563–3569 (2009).
Borg, C. et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J. Clin. Invest. 114, 379–388 (2004).
Sommer, G. et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc. Natl. Acad. Sci. USA 100, 6706–6711 (2003).
Rossi, F. et al. Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Proc. Natl. Acad. Sci. USA 103, 12843–12848 (2006).
Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).
Sato, E. et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl. Acad. Sci. USA 102, 18538–18543 (2005).
Quezada, S.A., Peggs, K.S., Curran, M.A. & Allison, J.P. CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J. Clin. Invest. 116, 1935–1945 (2006).
Hirschhorn-Cymerman, D. et al. OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J. Exp. Med. 206, 1103–1116 (2009).
Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).
Sharma, M.D. et al. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J. Clin. Invest. 117, 2570–2582 (2007).
Munn, D.H. & Mellor, A.L. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147–1154 (2007).
Curti, A. et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25− into CD25+ T regulatory cells. Blood 109, 2871–2877 (2007).
Baban, B. et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol. 183, 2475–2483 (2009).
Brenk, M. et al. Tryptophan deprivation induces inhibitory receptors ILT3 and ILT4 on dendritic cells favoring the induction of human CD4+CD25+ Foxp3+ T regulatory cells. J. Immunol. 183, 145–154 (2009).
Taguchi, T. et al. Conventional and molecular cytogenetic characterization of a new human cell line, GIST-T1, established from gastrointestinal stromal tumor. Lab. Invest. 82, 663–665 (2002).
Heinrich, M.C. et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J. Clin. Oncol. 26, 5352–5359 (2008).
Mellor, A.L. & Munn, D.H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).
Parmar, S. et al. Differential regulation of the p70 S6 kinase pathway by interferon alpha (IFNalpha) and imatinib mesylate (STI571) in chronic myelogenous leukemia cells. Blood 106, 2436–2443 (2005).
Kaur, S. et al. Regulatory effects of mammalian target of rapamycin-activated pathways in type I and II interferon signaling. J. Biol. Chem. 282, 1757–1768 (2007).
Kroczynska, B. et al. Interferon-dependent engagement of eukaryotic initiation factor 4B via S6 kinase (S6K)- and ribosomal protein S6K-mediated signals. Mol. Cell. Biol. 29, 2865–2875 (2009).
Kaur, S. et al. Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Proc. Natl. Acad. Sci. USA 105, 4808–4813 (2008).
Peggs, K.S., Quezada, S.A. & Allison, J.P. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol. Rev. 224, 141–165 (2008).
Katz, J.B., Muller, A.J. & Prendergast, G.C. Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol. Rev. 222, 206–221 (2008).
Pedicord, V.A., Montalvo, W., Leiner, I.M. & Allison, J.P. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc. Natl. Acad. Sci. USA 108, 266–271 (2011).
Klein, S., McCormick, F. & Levitzki, A. Killing time for cancer cells. Nat. Rev. Cancer 5, 573–580 (2005).
Seggewiss, R. et al. Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood 105, 2473–2479 (2005).
Lee, K.C. et al. Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia 24, 896–900 (2010).
Perez, D. et al. Cancer testis antigen expression in gastrointestinal stromal tumors: new markers for early recurrence. Int. J. Cancer 123, 1551–1555 (2008).
Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).
Larmonier, N. et al. Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL– tumors. J. Immunol. 181, 6955–6963 (2008).
Cohen, A.D. et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE 5, e10436 (2010).
Muller, A.J. et al. Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res. 70, 1845–1853 (2010).
Grohmann, U. et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med. 13, 579–586 (2007).
Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat. Med. 9, 1269–1274 (2003).
Chi, P. et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature 467, 849–853 (2010).
Okamoto, A. et al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin. Cancer Res. 11, 6030–6039 (2005).
Brandacher, G. et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin. Cancer Res. 12, 1144–1151 (2006).
Takao, M. et al. Increased synthesis of indoleamine-2,3-dioxygenase protein is positively associated with impaired survival in patients with serous-type, but not with other types of, ovarian cancer. Oncol. Rep. 17, 1333–1339 (2007).
Mokyr, M.B., Kalinichenko, T., Gorelik, L. & Bluestone, J. Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice. Cancer Res. 58, 5301–5304 (1998).
van Elsas, A., Hurwitz, A.A. & Allison, J.P. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 190, 355–366 (1999).
Hurwitz, A.A. et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 60, 2444–2448 (2000).
Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).
Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).
Curtin, J.A., Busam, K., Pinkel, D. & Bastian, B.C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 24, 4340–4346 (2006).
Flaherty, K.T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).
Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).
Hou, D.-Y. et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 67, 792–801 (2007).
Jasperson, L.K. et al. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114, 5062–5070 (2009).
Lee, H.J. et al. Rosmarinic acid inhibits indoleamine 2,3-dioxygenase expression in murine dendritic cells. Biochem. Pharmacol. 73, 1412–1421 (2007).
Cho, H. et al. Noninvasive multimodality imaging of the tumor microenvironment: registered dynamic magnetic resonance imaging and positron emission tomography studies of a preclinical tumor model of tumor hypoxia. Neoplasia 11, 247–259 (2009).
Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007).
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.
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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