Harnessing of the adaptive immune system, either by adoptive transfer of engineered T cells or by direct activation of endogenous T cells via checkpoint blockade, has yielded unprecedented clinical benefit in cancer. However, the full potential of these therapies is hampered by a system of elaborate molecular and cellular mechanisms that tumors orchestrate as they evolve to evade T-cell attack during metastatic cancer progression. These mechanisms, collectively referred to as the immune-suppressive tumor microenvironment, rely on cancer co-opting signaling pathways that regulate immunity in noncancer settings, including those implicated in normal physiology or in other disease states. Using an unbiased experimental approach to identify key drivers of cancer metastasis, apolipoprotein E (ApoE) was revealed as a regulator of cancer progression and tumor immunity. As tumors grow and metastasize, ApoE expression becomes silenced via the activity of a group of microRNAs that become switched on during cancer progression. The silencing of ApoE expression in tumors is associated with significantly greater metastatic potential, worse clinical prognosis, and increased accumulation of innate immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs). The ApoE pathway has previously been associated with the pathophysiology of atherosclerosis and Alzheimer’s disease, both of which are characterized histologically, in part, by aberrant inflammatory myeloid cell accumulation in the form of myeloid-derived foam cells and myeloid-derived microglia, respectively. In cancer, MDSCs accumulate in tumors and in the circulation, where they inhibit the activity of cytotoxic T cells via the expression of multiple immunosuppressive molecules. Their high abundance in the circulation has been associated with resistance to checkpoint blockade, highlighting their clinical relevance. MDSC abundance was found to be regulated via ApoE signaling through the ApoE receptor LRP8. Therapeutic activation of silenced ApoE expression can be accomplished pharmacologically by the administration of Liver X Receptor (LXR) agonists, which drive ApoE expression transcriptionally. RGX-104, a potent and selective LXR agonist, reversed cancer immune evasion in tumor models and in advanced cancer patients harboring a diverse array of refractory malignancies, including checkpoint inhibitor-refractory cancers. RGX-104 rapidly depleted MDSCs, resulting in restoration of antitumor immunity via activation of PD-1+ CD8+ T cells, which ultimately resulted in clinical antitumor activity.

Citation Format: Masoud Tavazoie. The LXR/ApoE pathway regulates the innate immune system in cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr IA11.