PD-1/PD-L1 blockade enhances T cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors
A partir d'une analyse d'échantillons tumoraux prélevés sur 85 patients atteints d'une tumeur stromale gastro-intestinale, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes suggérant l'intérêt d'immunothérapies anti PD1/PD-L1 pour renforcer l'efficacité de l'imatinib
Purpose: Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumor (GIST), 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 GIST.
Experimental Design: We analyzed tumor and matched blood samples from 85 patients with GIST 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 GIST.
Results: The inhibitory receptors PD-1, lymphocyte activation gene 3 (LAG-3), and T cell immunoglobulin mucin-3 (TIM-3) were upregulated on tumor-infiltrating T cells compared to 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 IFN-γ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+ mice imatinib downregulated IFN-γ-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 GIST. Collectively, our results provide the rationale to combine these agents in human GIST.
Clinical Cancer Research , résumé, 2015