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 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: Adrian M Seifert, Shan Zeng, Jennifer Q Zhang, Teresa S Kim, Noah A Cohen, Michael J Beckman, Benjamin D Medina, Joanna H Maltbaek, Jennifer K Loo, Megan H Crawley, Ferdinand Rossi, Peter Besmer, Cristina R Antonescu, Ronald P DeMatteo
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 2 Pg. 454-465 (Jan 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27470968 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• B7-H1 Antigen
• CD274 protein, human
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• STAT1 Transcription Factor
• STAT1 protein, human
• Imatinib Mesylate

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, immunology)
• B7-H1 Antigen (antagonists & inhibitors, immunology)
• Cell Line, Tumor
• Gastrointestinal Stromal Tumors (genetics, immunology, pathology, therapy)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Imatinib Mesylate (administration & dosage)
• Immunotherapy
• Lymphocyte Activation (drug effects)
• Mice
• Molecular Targeted Therapy
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• STAT1 Transcription Factor (antagonists & inhibitors, genetics)
• T-Lymphocytes (drug effects, immunology)
• Xenograft Model Antitumor Assays