Abstract
Axl is an oncogenic receptor tyrosine kinase that plays a role in many cancers. LIGHT (Lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells) is a ligand that induces robust anti-tumor immunity by enhancing the recruitment and activation of effector immune cells at tumor sites. We observed that mouse EL4 and human Jurkat T lymphoma cells that stably overexpressed Axl also showed high expression of LIGHT. When Jurkat-Axl cells were treated with Gas6, a ligand for Axl, LIGHT expression was upregulated through activation of the PI3K/AKT signaling pathway and transcriptional induction by Sp1. The lytic activity of cytotoxic T lymphocytes and natural killer cells was enhanced by EL4-Axl cells. In addition, tumor volume and growth were markedly reduced due to enhanced apoptotic cell death in EL4-Axl tumor-bearing mice as compared to control mice. We also observed upregulated expression of CCL5 and its receptor, CCR5, and enhanced intratumoral infiltration of cytotoxic T lymphocytes and natural killer cells in EL4-Axl-bearing mice as compared to mock controls. These data strongly suggested that Axl exerts novel tumor suppressor effects by inducing upregulation of LIGHT in the tumor microenvironment of T lymphoma.
Highlights
The mammalian TAM receptor tyrosine kinase family consists of three receptors, namely, Tyro-3, Axl and Mer [1]
RT-PCR and western blot analysis showed that the expression levels of both Axl and LIGHT were elevated in human Jurkat T lymphoma cells that stably overexpressed Axl compared to the mock control (Figure 1A)
Similar expression pattern was observed in mouse EL4-Axl T lymphoma cells (Figures 1C and 1D), implying that LIGHT expression may be regulated by Axl
Summary
The mammalian TAM receptor tyrosine kinase family consists of three receptors, namely, Tyro-3, Axl and Mer [1]. Axl was originally described as an oncogene isolated from chronic myeloid leukemia patients [5]. The Gas6/Axl signaling pathway regulates many cellular processes, such as cell proliferation, survival, migration and adhesion; blood clot stabilization; inflammation; cytokine release; and phagocytosis of apoptotic cells [11]. The Gas6/Axl signaling pathway suppresses apoptotic cell death through the inhibition of pro-apoptotic caspase 3 and phosphorylation of NF-κB [12]. ERK mediates Gas6-induced human prostate cancer cell proliferation suggesting that the Gas6/Axl signaling pathway may be involved in the tumor evasion mechanism by suppressing the pro-apoptotic effects of numerous chemotherapeutics in many human cancers [13]. A recent report demonstrated that Axl was constitutively phosphorylated in the primary B cells derived from chronic lymphocytic leukemia (CLL) patients and its expression correlated with the proliferation or apoptosis rate of CLL [17]. Axl transcripts were especially absent in T lymphoma patients
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