PCSK9-mediated degradation of cell-surface LDL receptors impairs human CD8+ T cell effector functions

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol via low-density lipoprotein receptors (LDLRs).
• Elevated PCSK9 expression correlates with poor survival in various cancers.
• PCSK9's role in T cell function and cancer immunity is largely unexplored.

Purpose of the Study:

• To investigate the hypothesis that PCSK9 degrades LDLRs on CD8+ T cells, impairing antitumor immunity.
• To identify PCSK9 as a potential therapeutic target for enhancing cancer immunotherapy.

Main Methods:

• Treatment of activated human CD8+ T cells with recombinant PCSK9.
• Assessment of surface LDLR and ICAM-1 expression, granzyme B secretion, and proliferation.
• Analysis of CD8+ T cells from patients with homozygous familial hypercholesterolemia.

Main Results:

• Recombinant PCSK9 reduced surface LDLR and ICAM-1 expression on CD8+ T cells.
• PCSK9 treatment decreased granzyme B secretion and proliferation in CD8+ T cells.
• PCSK9 inhibition or lipoprotein deprivation reversed PCSK9's effects, confirming LDLR dependence.
• CD8+ T cells from familial hypercholesterolemia patients showed impaired proliferation and ICAM-1 expression.

Conclusions:

• PCSK9 degrades LDLRs on CD8+ T cells, limiting cholesterol uptake and impairing T cell function.
• PCSK9 inhibition represents a potential strategy to enhance CD8+ T cell-mediated antitumor immunity.