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

Nature Medicine volume 17, pages 1094–1100 (2011)Cite this article

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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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References

  1. Rubin, B.P., Heinrich, M.C. & Corless, C.L. Gastrointestinal stromal tumour. Lancet 369, 1731–1741 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).

    Article  CAS  PubMed  Google Scholar 

  3. Heinrich, M.C. et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299, 708–710 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Demetri, G.D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Cameron, S. et al. Immune cells in primary gastrointestinal stromal tumors. Eur. J. Gastroenterol. Hepatol. 20, 327–334 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

  8. 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).

    Article  PubMed  Google Scholar 

  9. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Munn, D.H. & Mellor, A.L. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147–1154 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. Baban, B. et al. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J. Immunol. 183, 2475–2483 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  PubMed  Google Scholar 

  23. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mellor, A.L. & Munn, D.H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. Klein, S., McCormick, F. & Levitzki, A. Killing time for cancer cells. Nat. Rev. Cancer 5, 573–580 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, K.C. et al. Lck is a key target of imatinib and dasatinib in T-cell activation. Leukemia 24, 896–900 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Perez, D. et al. Cancer testis antigen expression in gastrointestinal stromal tumors: new markers for early recurrence. Int. J. Cancer 123, 1551–1555 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Muller, A.J. et al. Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res. 70, 1845–1853 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Grohmann, U. et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med. 13, 579–586 (2007).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. Chi, P. et al. ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours. Nature 467, 849–853 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. 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).

    CAS  PubMed  Google Scholar 

  46. 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).

    CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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).

    CAS  PubMed  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. Hodi, F.S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    Article  CAS  PubMed  Google Scholar 

  52. Flaherty, K.T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467, 596–599 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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).

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lee, H.J. et al. Rosmarinic acid inhibits indoleamine 2,3-dioxygenase expression in murine dendritic cells. Biochem. Pharmacol. 73, 1412–1421 (2007).

    Article  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sotillo, R. et al. Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 11, 9–23 (2007).

    Article  CAS  PubMed  Google Scholar 

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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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Authors and Affiliations

  1. Department of Surgery, Memorial Hospital, New York, New York, USA

    Vinod P Balachandran, Michael J Cavnar, Shan Zeng, Zubin M Bamboat, Lee M Ocuin, Hebroon Obaid, Eric C Sorenson, Rachel Popow, Charlotte Ariyan & Ronald P DeMatteo

  2. Developmental Biology Program, Sloan-Kettering Institute, New York, New York, USA

    Ferdinand Rossi & Peter Besmer

  3. Department of Pathology, Memorial Hospital, New York, New York, USA

    Tianhua Guo & Cristina R Antonescu

  4. Division of Human Health and Medical Science, Graduate School of Kuroshio Science, Kochi University, Kochi, Japan

    Takahiro Taguchi

  5. The Ludwig Center for Cancer Immunotherapy, New York, New York, USA

    Jianda Yuan, Jedd D Wolchok & James P Allison

  6. Department of Medicine, Memorial Hospital, New York, New York, USA

    Jedd D Wolchok

  7. Immunology Program, Sloan-Kettering Institute, New York, New York, USA

    James P Allison

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  1. Vinod P Balachandran
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Contributions

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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