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

AM Seifert, S Zeng, JQ Zhang, TS Kim, NA Cohen… - Clinical Cancer …, 2017 - AACR
AM Seifert, S Zeng, JQ Zhang, TS Kim, NA Cohen, MJ Beckman, BD Medina, JH Maltbaek
Clinical Cancer Research, 2017AACR
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 …
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.
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