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

Qi-Chao Yang; Shuo Wang; Yuan-Tong Liu; An Song; Zhi-Zhong Wu; Shu-Cheng Wan; Hui-Min Li; Zhi-Jun Sun

doi:10.1016/j.isci.2023.106916

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

iScience. 2023 May 19;26(6):106916. doi: 10.1016/j.isci.2023.106916. eCollection 2023 Jun 16.

Authors

Qi-Chao Yang¹, Shuo Wang¹, Yuan-Tong Liu¹, An Song¹, Zhi-Zhong Wu¹, Shu-Cheng Wan¹, Hui-Min Li¹, Zhi-Jun Sun^{1

2}

Affiliations

¹ The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.
² Department of Oral and Maxillofacial Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been demonstrated to play a critical role in regulating cholesterol homeostasis and T cell antitumor immunity. 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 antitumor 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.

Keywords: Cancer; Immune response; Immunology; Molecular biology.