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

Abstract

Cholesterol facilitated the formation of T cell receptor on cytotoxic CD8+ T lymphocytes (CTLs). However, the activation of CD8+ T cells always resulted in the upregulation of acetyl-CoA acetyltransferase-1 (ACAT-1) and enhanced the esterification of cholesterol. To relieve the suppression on CD8+ T cells, an ACAT-1 inhibitor avasimibe was combined with chemo-immunotherapy. Paclitaxel and immunoadjuvant αGC were co-encapsulated in liposomes modified with pH sensitive TH peptide (PTX/αGC-TH-Lip). After intravenous injections, the combination of avasimibe significantly elevated the free cholesterol level and relieved the inhibition of CD8+ T cells caused by PTX/αGC-TH-Lip, leading to enhanced CTL responses and anti-tumor effects of PTX/αGC-TH-Lip in B16F10 melanoma xenograft and lung metastasis models. The adoptive immunotherapy further confirmed the enhanced anti-tumor immune responses of the combined strategy. The combination of avasimibe and PTX/αGC-TH-Lip was proven as a feasible approach to enhance the antitumor effects of chemo-immunotherapy by relieving the inhibition of CD8+ T cells.

• Authors: Man Li, Yuting Yang, Jiaojie Wei, Xingli Cun, Zhengze Lu, Yue Qiu, Zhirong Zhang, Qin He
• Journal: Nanomedicine : nanotechnology, biology, and medicine (Nanomedicine) Vol. 14 Issue 8 Pg. 2541-2550 (11 2018) ISSN: 1549-9642 [Electronic] United States
• PMID: 30193815 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Acetamides
• Acetates
• Antineoplastic Agents, Phytogenic
• Cell-Penetrating Peptides
• Cytochrome P-450 CYP3A Inducers
• Liposomes
• Sulfonamides
• Sulfonic Acids
• avasimibe
• Cholesterol
• Acat1 protein, mouse
• Acetyl-CoA C-Acetyltransferase
• Paclitaxel

Topics

• Acetamides
• Acetates (pharmacology)
• Acetyl-CoA C-Acetyltransferase (antagonists & inhibitors)
• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis
• CD8-Positive T-Lymphocytes (drug effects, immunology, pathology)
• Cell Proliferation
• Cell-Penetrating Peptides (administration & dosage, chemistry)
• Cells, Cultured
• Cholesterol (chemistry, metabolism)
• Cytochrome P-450 CYP3A Inducers (pharmacology)
• Esterification
• Female
• Humans
• Immunotherapy, Adoptive
• Liposomes (administration & dosage, chemistry)
• Lung Neoplasms (immunology, metabolism, secondary, therapy)
• Melanoma, Experimental (immunology, metabolism, pathology, therapy)
• Mice
• Mice, Inbred C57BL
• Paclitaxel (pharmacology)
• Sulfonamides
• Sulfonic Acids (pharmacology)
• T-Lymphocytes, Cytotoxic (drug effects, immunology, pathology)