PD-1/PD-L1 blockade enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors Journal Article

Authors: Seifert, A. M.; Zeng, S.; Zhang, J. Q.; Kim, T. S.; Cohen, N. A.; Beckman, M. J.; Medina, B. D.; Maltbaek, J. H.; Loo, J. K.; Crawley, M. H.; Rossi, F.; Besmer, P.; Antonescu, C. R.; DeMatteo, R. P.
Article Title: PD-1/PD-L1 blockade enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors
Abstract: Purpose: 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. Experimental Design: 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 KitV558D/+ 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 IFNg-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558D/+ mice, imatinib downregulated IFNgrelated 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. © 2016 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 23
Issue: 2
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2017-01-15
Start Page: 454
End Page: 465
Language: English
DOI: 10.1158/1078-0432.ccr-16-1163
PROVIDER: scopus
PMCID: PMC5241182
PUBMED: 27470968
Notes: Article -- Export Date: 2 March 2017 -- Source: Scopus
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MSK Authors
  1. Ronald P DeMatteo
    597 DeMatteo
  2. Cristina R Antonescu
    606 Antonescu
  3. Ferdinando Rossi
    19 Rossi
  4. Shan Zeng
    22 Zeng
  5. Peter Besmer
    81 Besmer
  6. Teresa Sora Kim
    23 Kim
  7. Megan Hannon Crawley
    11 Crawley
  8. Noah Avram Cohen
    15 Cohen
  9. Adrian Marcel Seifert
    13 Seifert
  10. Jennifer Qi Zhang
    13 Zhang
  11. Benjamin Medina
    7 Medina
  12. Jennifer Loo
    9 Loo