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

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.

FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner

“…APOE is significantly highly expressed in lung cancer, and its overexpression promotes cancer proliferation and migration, and aggressiveness of lung cancer [ 43 ]. APOE knockout inhibits tumor growth and metastasis by increasing REEM-1-mediated infiltration of NK cells in lung cancer [ 44 ]. Notably, APOE modulates brain glucose metabolism in AD [ 45 ], and affects glucose uptake in atherosclerosis [ 46 ].…”

Inhibition of APOE potentiates immune checkpoint therapy for cancer

“…According to Kemp Samantha B et al 10 , orthotopic implantation of mouse pancreatic ductal adenocarcinoma (PDA) cells into syngeneic wild type or in Apoe -/- mice showed reduced tumor growth in Apoe -/- mice. Lee Yong Sun et al 11 found that urethane-induced lung tumor incidence and B16F10 lung metastasis in Apoe -/- mice were significantly reduced in comparison to that in WT mice. Buss Linda A et al 12 reported that Apoe -/- mice also had a reduced rate of metastasis compared to WT mice implanted with EO771 murine breast cancer cells.…”

Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1)

“…In addition, this molecule has been recently reported to be required for successful NK cell anti-tumor activity in a mouse lung tumor model. Lee et al [245] demonstrated that lung tumor development and metastasis were suppressed via an increase in TREM-1-dependent NK cell cytotoxicity. TREM-1 blockade with LP-17 prevented NK cell killing, whereas TREM-1 mAb recovered NK cytotoxic effects.…”