ITK inhibition induced in vitro and in vivo anti-tumor activity through downregulating TCR signaling pathway in malignant T cell lymphoma

Yalu Liu,Yunfei Shi,Yuqin Song,Ning Ding,Wen Zheng,Jun Zhu,Yan Xie,Zhengying Pan,Meifeng Tu,Ningjing Lin,Xi Wang,Zhitao Ying,Lijuan Deng,Weiping Liu,Lingyan Ping,Xiaopei Wang,Chen Zhang,Xiaogan Wang

doi:10.1186/s12935-019-0754-9

Abstract

BackgroundAngioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. However, the molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown.MethodsAntibodies specific to phosphorylated ZAP70, ITK and PLCγ1 were used to identify the activation status of intracellular proteins involved in TCR signaling in AITL patients. Malignant T cell lymphoma cells were transduced with a lentiviral construct containing ITK shRNA for cellular and functional assays. The antitumor effects of the selective ITK inhibitor BMS-509744 were determined in vitro and in vivo.ResultsImmunohistochemistry staining showed that more than half of the AITL patients (n = 38) exhibited continuously activated intracellular TCR signaling pathway. Patients positive for phosphorylated ITK showed a lower rate of complete response (20% vs. 75%, P = 0.004) and a shorter progression-free survival (5.17 months vs. 25.1 months, P = 0.022) than patients negative for phosphorylated ITK. Genetic and pharmacological cellular ITK inhibition significantly compromised the proliferation, invasion and migration of malignant T cells. The selective ITK inhibitor BMS-509744 also induced the pro-apoptotic effects and G2/M phase cell cycle arrest in vitro and in vivo. Finally, inhibition of ITK synergistically enhanced the antitumor effect of vincristine and doxorubicin on malignant T cell lymphoma cell lines.ConclusionsOur findings suggest that ITK may be a novel candidate therapeutic target for the treatment of patients with ITK-expressing malignant T-cell lymphomas.

Highlights

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes
Twenty (54%) patients presented with B symptoms, twenty-five (69.4%) patients presented with elevated serum lactate dehydrogenase (LDH) and nineteen (59.4%) patients showed elevated β2-MG levels
To investigate the possible role of the T cell receptor (TCR) signaling pathway in the pathogenesis of T cell lymphoid malignancies, the phosphorylation status of key regulatory tyrosine kinases was analyzed in sections of tumor tissues from 38 AITL patients

Summary

Introduction

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma and associated with poor outcomes. The activation status of T cell receptor (TCR) signaling has recently become a focus of attention in terms of the therapeutic targets. The molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown. Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype that accounts for approximately 15% to 20% of peripheral T cell lymphomas (PTCLs) [1, 2]. Patients with PTCL are frequently diagnosed at an advanced stage (III–IV), resulting in poor outcomes and 5-year overall survival (OS) rates ranging from 25% to 30% [1, 5]. Next-Generation Sequencing detected highly recurrent somatic mutations including GTPase RHOA and epigenetic regulators, which pinpointing novel candidates for the investigation of targeted therapies in AITL

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