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

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.