Imatinib Potentiates Antitumor T Cell Responses in Gastrointestinal Stromal Tumor Through the Inhibition of Ido

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2011 Aug 30

PMID 21873989

Citations 285

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Cancer-associated fibroblasts as therapeutic targets for cancer: advances, challenges, and future prospects.

Cao Z, Quazi S, Arora S, Osellame L, Burvenich I, Janes P J Biomed Sci. 2025; 32(1):7.

PMID: 39780187 PMC: 11715488. DOI: 10.1186/s12929-024-01099-2.

Gastrointestinal Stromal Tumor of the Rectum: Report of a Case With Long-Term Imatinib Treatment.

Tripathi M, Purwar R, Sinha R, Singh P, Pandey M Cureus. 2024; 16(11):e74269.

PMID: 39717333 PMC: 11663722. DOI: 10.7759/cureus.74269.

Genomic and transcriptomic landscape of human gastrointestinal stromal tumors.

Xie F, Luo S, Liu D, Lu X, Wang M, Liu X Nat Commun. 2024; 15(1):9495.

PMID: 39489749 PMC: 11532483. DOI: 10.1038/s41467-024-53821-1.

Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF/CXCR4 axis to immune escape.

Xiao S, Xu R, Yang Y, Zhao R, Xie Y, Lei X Front Immunol. 2024; 15:1431535.

PMID: 39464891 PMC: 11502962. DOI: 10.3389/fimmu.2024.1431535.

Impact of systemic steroids on the efficacy of first line imatinib treatment of patients with advanced gastrointestinal stromal tumors (GISTs).

Kim S, Kim H, Kim E, Ryu M, Kang Y BMC Cancer. 2024; 24(1):1245.

PMID: 39379868 PMC: 11463065. DOI: 10.1186/s12885-024-13032-9.

References

Jasperson L, Bucher C, Panoskaltsis-Mortari A, Mellor A, Munn D, Blazar B . Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood. 2009; 114(24):5062-70. PMC: 2788979. DOI: 10.1182/blood-2009-06-227587. View

Seggewiss R, Lore K, Greiner E, Magnusson M, Price D, Douek D . Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner. Blood. 2004; 105(6):2473-9. DOI: 10.1182/blood-2004-07-2527. View

Heinrich M, Corless C, Duensing A, McGreevey L, Chen C, Joseph N . PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003; 299(5607):708-10. DOI: 10.1126/science.1079666. View

Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C . Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006; 12(4):1144-51. DOI: 10.1158/1078-0432.CCR-05-1966. View

Pedicord V, Montalvo W, Leiner I, Allison J . Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci U S A. 2010; 108(1):266-71. PMC: 3017182. DOI: 10.1073/pnas.1016791108. View

Sato E, Olson S, Ahn J, Bundy B, Nishikawa H, Qian F . 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 U S A. 2005; 102(51):18538-43. PMC: 1311741. DOI: 10.1073/pnas.0509182102. View

Cho H, Ackerstaff E, Carlin S, Lupu M, Wang Y, Rizwan A . 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. 2009; 11(3):247-59, 2p following 259. PMC: 2647727. DOI: 10.1593/neo.81360. View

Hirschhorn-Cymerman D, Rizzuto G, Merghoub T, Cohen A, Avogadri F, Lesokhin A . OX40 engagement and chemotherapy combination provides potent antitumor immunity with concomitant regulatory T cell apoptosis. J Exp Med. 2009; 206(5):1103-16. PMC: 2715041. DOI: 10.1084/jem.20082205. View

Rossi F, Ehlers I, Agosti V, Socci N, Viale A, Sommer G . Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci U S A. 2006; 103(34):12843-8. PMC: 1568935. DOI: 10.1073/pnas.0511076103. View

10.

Quezada S, Peggs K, Curran M, Allison J . CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells. J Clin Invest. 2006; 116(7):1935-45. PMC: 1479425. DOI: 10.1172/JCI27745. View

11.

Kaur S, Sassano A, Dolniak B, Joshi S, Majchrzak-Kita B, Baker D . Role of the Akt pathway in mRNA translation of interferon-stimulated genes. Proc Natl Acad Sci U S A. 2008; 105(12):4808-13. PMC: 2290753. DOI: 10.1073/pnas.0710907105. View

12.

Borg C, Terme M, Taieb J, Menard C, Flament C, Robert C . Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest. 2004; 114(3):379-88. PMC: 489961. DOI: 10.1172/JCI21102. View

13.

Menard C, Blay J, Borg C, Michiels S, Ghiringhelli F, Robert C . Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 2009; 69(8):3563-9. DOI: 10.1158/0008-5472.CAN-08-3807. View

14.

Demetri G, von Mehren M, Blanke C, Van Den Abbeele A, Eisenberg B, Roberts P . Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002; 347(7):472-80. DOI: 10.1056/NEJMoa020461. View

15.

Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S . Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998; 279(5350):577-80. DOI: 10.1126/science.279.5350.577. View

16.

Katz J, Muller A, Prendergast G . Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape. Immunol Rev. 2008; 222:206-21. DOI: 10.1111/j.1600-065X.2008.00610.x. View

17.

Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G . Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2007; 8(1):59-73. DOI: 10.1038/nri2216. View

18.

Cameron S, Haller F, Dudas J, Moriconi F, Gunawan B, Armbrust T . Immune cells in primary gastrointestinal stromal tumors. Eur J Gastroenterol Hepatol. 2008; 20(4):327-34. DOI: 10.1097/MEG.0b013e3282f3a403. View

19.

Muller A, DuHadaway J, Jaller D, Curtis P, Metz R, Prendergast G . Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res. 2010; 70(5):1845-53. PMC: 3176890. DOI: 10.1158/0008-5472.CAN-09-3613. View

20.

Taguchi T, Sonobe H, Yamasaki I, Shuin T, Takano A, Araki K . Conventional and molecular cytogenetic characterization of a new human cell line, GIST-T1, established from gastrointestinal stromal tumor. Lab Invest. 2002; 82(5):663-5. DOI: 10.1038/labinvest.3780461. View