Targeting PCSK9 reduces cancer cell stemness and enhances antitumor immunity in head and neck cancer

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been demonstrated to play a critical role in regulating cholesterol homeostasis and T cell antitumor im-munity. However, the expression, function, and therapeutic value of PCSK9 in head and neck squamous cell carcinoma (HNSCC) remain largely unexplored. Here, we found that the expression of PCSK9 was upregulated in HNSCC tissues, and higher PCSK9 expression indicated poorer prognosis in HNSCC patients. We further found that pharmacological inhibition or siRNA downregulating PCSK9 expression suppressed the stemness-like phenotype of cancer cells in an LDLR-dependent manner. Moreover, PCSK9 inhibition enhanced the infiltration of CD8(+) T cells and reduced the myeloid-derived suppressor cells (MDSCs) in a 4MOSC1 syngeneic tumor-bearing mouse model, and it also enhanced the anti-tumor effect of anti-PD-1 immune checkpoint blockade (ICB) therapy. Together, these results indicated that PCSK9, a traditional hypercholesterolemia target, may be a novel biomarker and therapeutic target to enhance ICB therapy in HNSCC.

Automated summary

PCSK9 expression is upregulated in HNSCC tissues and higher expression is associated with poorer prognosis. Inhibition of PCSK9 suppresses cancer cell stemness via LDLR-dependent mechanism. PCSK9 inhibition enhances CD8(+) T cell infiltration, reduces MDSCs, and improves the efficacy of anti-PD-1 ICB therapy in HNSCC.