Abstract
Myeloid-derived suppressor cells (MDSCs) in mouse are inflammatory cells that play critical roles in promoting cancer growth and metastasis by directly stimulating cancer cell proliferation and suppressing immune surveillance. In order to facilitate characterization of biochemical and cellular mechanisms of MDSCs, it is urgent to establish an “MDSC-like” cell line. By cross breeding of immortomouse (simian virus 40 large T antigen transgenic mice) with wild type and lysosomal acid lipase (LAL) knock-out (lal-/-) mice, we have established a wild type (HD1A) and a lal-/- (HD1B) myeloid cell lines. Compared with HD1A cells, HD1B cells demonstrated many characteristics similar to lal-/- MDSCs. HD1B cells exhibited increased lysosomes around perinuclear areas, dysfunction of mitochondria skewing toward fission structure, damaged membrane potential, and increased ROS production. HD1B cells showed increased glycolytic metabolism during blockage of fatty acid metabolism to fuel the energy need. Similar to lal-/- MDSCs, the mTOR signal pathway in HD1B cells is overly activated. Rapamycin treatment of HD1B cells reduced ROS production and restored the mitochondrial membrane potential. HD1B cells showed much stronger immunosuppression on CD4+ T cell proliferation and function in vitro, and enhanced cancer cells proliferation. Knockdown of mTOR with siRNA reduced the HD1B cell ability to immunosuppress T cells and stimulate cancer cell proliferation. Therefore, the HD1B myeloid cell line is an “MDSC-like” cell line that can be used as an alternative in vitro system to study how LAL controls various myeloid cell functions.
Highlights
Myeloid-derived suppressor cells (MDSCs) are myeloid progenitors that are blocked to further differentiate into granulocytes, macrophages, and dendritic cells at various pathogenic conditions [1,2]
The malfunction of HD1B was assessed by several molecules that are involved in fatty acid uptake and function, including CD36, forkhead box O (FoxO3), and SIRT1
We investigated another important group of fatty acid (FA) transporters, carnitine palmitoyl transferase (CPT1a, CPT1b and CPT1c) that transports long-chain FA into the mitochondria and are a rate limiting step of mitochondrial fatty-acid oxidation (FAO)
Summary
Myeloid-derived suppressor cells (MDSCs) are myeloid progenitors that are blocked to further differentiate into granulocytes, macrophages, and dendritic cells at various pathogenic conditions [1,2]. MDSCs in the tumor microenvironment have been suggested to have a causative role in directly stimulating cancer. MDSC-Like Cells cell proliferation and promoting tumor-associated immune suppression. Fatty acid metabolism supports both the biosynthetic and bioenergetic requirements of cell proliferation and survival. Increased CD14+CD16+ and CD14+CD33+ cells have been linked to heterozygote carriers of LAL mutations in humans [3]. Lal-/- MDSCs directly stimulate cancer cell proliferation [11], and suppress T cell proliferation and impair T cell function [12]. Myeloid-specific expression of human LAL in lal-/- mice reverses tissue inflammation, MDSCs infiltration, and corrects malformation and dysfunction of MDSCs [13,14]
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