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.
authors.affiliation: Department of Surgery, Memorial Hospital, New York, New York, USA.
authors.forename: Vinod P
authors.initials: VP
authors.lastname: Balachandran
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cavnar
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.forename: Zubin M
authors.initials: ZM
authors.lastname: Bamboat
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ocuin
authors.forename: Hebroon
authors.initials: H
authors.lastname: Obaid
authors.forename: Eric C
authors.initials: EC
authors.lastname: Sorenson
authors.forename: Rachel
authors.initials: R
authors.lastname: Popow
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ariyan
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.forename: Tianhua
authors.initials: T
authors.lastname: Guo
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Takahiro
authors.initials: T
authors.lastname: Taguchi
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
mesh_terms: D000818:Animals; D001549:Benzamides; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D007167:Immunotherapy / Q000379:methods*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D001549:Benzamides; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit