Abstract 161: Activation of mTOR pathway in myeloid-derived suppressor cells with lysosomal acid lipase deficiency stimulates cancer cell proliferation and metastasis

Abstract

Abstract Inflammation plays crucial roles at all stages of tumor development, from tumor initiation to metastatic progression, during which myeloid-derived suppressor cells (MDSCs) are an important participant. Although MDSCs are known to suppress immune surveillance, their roles in directly stimulating cancer cell proliferation and metastasis currently remains unclear. Lysosomal acid lipase (LAL) deficiency causes systemic expansion and infiltration of MDSCs in multiple organs and subsequent inflammation. In the LAL-deficient (lal-/-) mouse model, we found that melanoma metastasized massively in allogeneic lal-/- mice, which was suppressed in allogeneic lal+/+ mice due to immune rejection. Therefore, we hypothesized that MDSCs with LAL deficiency directly stimulate cancer cell proliferation and metastasis. Bone marrow-derived MDSCs from lal-/- mice directly stimulated B16 melanoma cell proliferation in vitro by co-culture analysis and in vivo by co-implantation in the Matrigel plugs. These tumor cell-stimulatory effects were diminished when myeloid-specific human LAL (hLAL) was expressed in myeloid cells in lal-/- mice. In addition, lal-/- MDSCs facilitated B16 melanoma cell metastasis in the lungs of recipient lal+/+ mice via tail vein injection. Furthermore, the mammalian target of rapamycin (mTOR) and its downstream gene products were significantly up-regulated in lal-/- MDSCs. Knockdown of mTOR in lal-/- MDSCs suppressed their stimulation on B16 melanoma cell proliferation, growth and metastasis, indicating the tumor-promoting function of lal-/- MDSCs is mediated, at least in part, through over-activation of the mTOR pathway. Finally, lal-/- MDSCs stimulated proliferation and growth of Lewis lung carcinoma (LLC), and transgenic mouse prostate cancer (TRAMP-C2) cells, and these effects were impaired after mTOR inhibition. Our results indicate that LAL plays a critical role in regulating MDSCs ability to directly stimulate cancer cell proliferation, and overcome immune rejection of cancer metastasis in allogeneic mice through modulation of the mTOR pathway, which provides a mechanistic basis for targeting MDSCs to reduce the risk of cancer metastasis. Therefore, MDSCs possess dual functions to facilitate cancer metastasis: suppress immune surveillance, and stimulate cancer cell proliferation and growth. Citation Format: Ting Zhao, Hong Du, Xinchun Ding, Katlin Walls, Cong Yan. Activation of mTOR pathway in myeloid-derived suppressor cells with lysosomal acid lipase deficiency stimulates cancer cell proliferation and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 161. doi:10.1158/1538-7445.AM2014-161