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

## TL;DR

This study shows that PCSK9 reduces LDL receptors on CD8+ T cells, impairing their ability to fight cancer by limiting cholesterol uptake and key immune functions.

## Contribution

The study reveals a novel role of PCSK9 in suppressing CD8+ T cell function through LDLR degradation, linking cholesterol metabolism to antitumor immunity.

## Key findings

- PCSK9 treatment reduces surface LDLR and ICAM-1 expression in CD8+ T cells.
- PCSK9 inhibition or lipoprotein deprivation reverses the negative effects on T cell function.
- CD8+ T cells with defective LDLR signaling show reduced activation and proliferation.

## Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates circulating cholesterol levels by binding hepatic low-density lipoprotein (LDL) receptors (LDLRs) and directing them to lysosomal degradation. Beyond the liver, PCSK9 expression in multiple cancers, including colorectal, hepatocellular, and head and neck carcinomas, correlates with poor survival. We hypothesized that PCSK9 promotes LDLR degradation on CD8+ T cells, limiting cholesterol uptake and impairing antitumor immunity. Treatment of activated human CD8+ T cells from healthy donors with recombinant PCSK9 reduced surface LDLR and ICAM-1 expression, granzyme B secretion, and proliferation. The effects of PCSK9 treatment were reversed by PCSK9 inhibition or by culturing cells under lipoprotein-deprived conditions, confirming LDLR dependence. CD8+ T cells from patients with homozygous familial hypercholesterolemia, who harbor inactivating LDLR mutations, exhibited reduced proliferation and ICAM-1 expression upon activation. Together, these findings identify PCSK9 as a potential therapeutic target to enhance CD8+ T cell-mediated antitumor immunity.

•Tumor-infiltrating lymphocytes exhibit dysregulated cholesterol metabolism•Secreted PCSK9 downregulates cell surface LDL receptors on CD8+ T cells•PCSK9 exposure decreases ICAM-1 expression and granzyme B secretion by CD8+ T cells•CD8+ T cells with defective LDL receptor signaling show reduced functional capacity

Tumor-infiltrating lymphocytes exhibit dysregulated cholesterol metabolism

Secreted PCSK9 downregulates cell surface LDL receptors on CD8+ T cells

PCSK9 exposure decreases ICAM-1 expression and granzyme B secretion by CD8+ T cells

CD8+ T cells with defective LDL receptor signaling show reduced functional capacity

Immunology; Cell biology