title: PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors.
abstract: OBJECTIVE
  Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs.
  
  
  METHODS
  We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Δ/+mice that develop GISTs.
  
  
  RESULTS
  The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition.
  
  
  CONCLUSIONS
  PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454-65. ©2016 AACR.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Seifert
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shan
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jennifer Q
authors.initials: JQ
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Cohen
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Beckman
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Medina
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Joanna H
authors.initials: JH
authors.lastname: Maltbaek
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Loo
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Megan H
authors.initials: MH
authors.lastname: Crawley
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.|Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Rossi
authors.affiliation: Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Besmer
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. dematter@mskcc.org.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: DeMatteo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology*; D045744:Cell Line, Tumor; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D058990:Molecular Targeted Therapy; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000068877:Imatinib Mesylate