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

Abstract

Background 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. However, the molecular pathogenesis mechanisms and novel therapeutic targets are largely unknown. Methods Antibodies 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. Results Immunohistochemistry 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. Conclusions Our findings suggest that ITK may be a novel candidate therapeutic target for the treatment of patients with ITK-expressing malignant T-cell lymphomas. Electronic supplementary material The online version of this article (10.1186/s12935-019-0754-9) contains supplementary material, which is available to authorized users.

Engagement of lymphoma T cell receptors causes accelerated growth and the secretion of an NK cell-inhibitory factor

“…A disruption of the interactions between antigen-presenting cells and T cell lymphomas may decrease lymphoma growth rates and may attenuate lymphoma-induced NK cell inhibitions. Also, drugs that interfere with cascades downstream of the TCR such as ITK inhibitors may produce similar outcomes [ 16 ]. Lastly, boosting NK cell numbers and/or functions in vivo [ 17 ] or transferring ex vivo-expanded NK cells as applied to patients with AML [ 18 ] may also be of use in the treatment of T cell lymphomas.…”

Machine learning analysis of gene expression profile reveals a novel diagnostic signature for osteoporosis

“…Previous studies have revealed that a compound heterozygous missense mutation and a large deletion in the KCTD7 gene presenting as an opsoclonus-myoclonus ataxia-like syndrome [ 35 ]. In addition, Liu et al demonstrated that the inhibition of ITK can induce anti-tumor activity by downregulating TCR signaling pathway in malignant T cell lymphoma both in vitro and in vivo [ 36 ]. All these researches indicated that these 9 optimal genes might be involved in the occurrence and development of human diseases including OP.…”

Rationale for the combination of venetoclax and ibrutinib in T-prolymphocytic leukemia

“…Intracellular T-cell receptor signaling via increased phospho-ITK expression is known to be associated with inferior prognosis in T-cell lymphomas, and ITK inhibition has been shown to prime apoptosis of malignant T cells by downregulating anti-apoptotic proteins, including Bcl-2, MCL-1, and Bcl-XL. 12 At the protein level, in patient A expression of Mcl-1 and Bcl-2 was induced during venetoclax monotherapy, but was reduced upon combinatorial treatment. In contrast, patient B showed a predominant induction of pro-apoptotic BH3 family members in response to combined ibrutinib and venetoclax treatment ( Online Supplementary Figure S3C and D ).…”