Inhibition of Lung Tumor Development in ApoE Knockout Mice via Enhancement of TREM-1 Dependent NK Cell Cytotoxicity.

Yong Sun Lee,Sang-Bae Han,Ki Cheon Kim,Jin Tae Hong,In Jun Yeo

doi:10.3389/fimmu.2019.01379

Abstract

Apolipoprotein E (ApoE) is known to regulate lipid homeostasis and associated with atherosclerogenesis. Eventhough atherosclerogenesis is associated with tumor development, the role of ApoE in lung tumorigenesis and metastasis is not clear. Thus, the tumor growth and metastasis were compared in WT and ApoE knockout (KO) mice. Urethane-induced lung tumor incidence and B16F10 lung metastasis in ApoE knockout (KO) mice were significantly reduced in comparison to that in WT mice. Knockdown of ApoE expression in lung cancer cells and B16F10 cells also decreased cancer cell growth and metastasis. The inhibitory effect of ApoE KO on tumor development and metastasis was associated with increase of infiltration of NK cells. NK cells derived from ApoE KO mice showed much greater cytotoxicity than those from WT mice. These cytotoxic effect of NK cells derived from ApoE KO mice was associated with higher expression of Granzyme B, Fas Ligand, IFN-γ, TNF-α, NKG2D, NKp46, and DNAM-1 expression. Triggering receptor expressed on myeloid cell (TREM)-1 is a proinflammatory mediator expressed on NK cells, and is known to be associated with NK cell cytotoxicity. Thus, we investigated the role of TREM-1 on ApoE KO mice originated NK cell mediated cytotoxicity for cancer cells. Blockade of TREM-1 expression with a TREM-1 antagonist prevented NK cell-mediated cytotoxicity. TREM-1 antibody recovered cytotoxic effect of NK cells derived from KO mice of T-bet, which upregulating gene for TREM-1. These data indicate that ApoE KO suppressed lung tumor development and metastasis via increase of TREM-1-dependent anti-tumor activity of NK cells.

Highlights

As one of the most common malignancies, lung cancer is a leading cause of death, and is expected to cause increased future mortality [1]
We intravenously injected an identical number of melanoma cells (B16F10) into Apolipoprotein E (ApoE) KO and WT mice fed with normal diet (ND) or high-fat diet (HFD) and quantified metastatic lesions in the lungs after 3 weeks
Cholesterol did not affect cell proliferation in lung cancer cells (A549 and NCI-H460) and B16F10 mouse melanoma cells (Supplementary Figure 1). These data suggest that the inhibition of tumor growth and metastasis in ApoE KO mice may not be related to the cholesterol level itself, but could be associated with the physiological effects of apoptotic protein was increased in HFD-fed ApoE KO mice of ApoE

Summary

Introduction

As one of the most common malignancies, lung cancer is a leading cause of death, and is expected to cause increased future mortality [1]. The majority of lung cancers originate from epithelial cells and can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), morphologically. NSCLC is predominant type of lung cancer and accounts for about 85% of lung cancers [2]. Smoking is the primary cause of most lung cancer cases, approximately 10–15% are caused by genetics and other factors including nutritional factors [3]. Dietary cholesterol is associated with an increased risk of lung cancer [4].

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