Enhanced chemo-immunotherapy against melanoma by inhibition of cholesterol esterification in CD8+ T cells

Chemotherapeutic paclitaxel and immunoadjuvant αGC were co-encapsulated in liposomes modified with pH sensitive TH peptide (PTX/αGC-TH-Lip) to initiate tumor apoptosis and anti-tumor immune responses. However, acetyl-CoA acetyltransferase-1 (ACAT-1), a cholesterol esterification enzyme, was upregulated in activated CD8+ T cells, which lowered the cholesterol level and impaired the formation of TCR. ACAT-1 inhibitor avasimibe was combined with PTX/αGC-TH-Lip to relieve the suppression and further promote the antitumor responses. After intravenous injections, the combined therapy elevated the free cholesterol level and enhanced the anti-tumor immune responses in B16F10 melanoma xenograft and lung metastasis models.201