PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is implicated in cholesterol homeostasis and cancer promotion.
• The specific roles and mechanisms of PCSK9 in melanoma tumorigenesis remain largely undefined.

Purpose of the Study:

• To investigate the oncogenic functions of PCSK9 in melanoma.
• To elucidate the association between PCSK9, cholesterol metabolism, and immune evasion in melanoma.
• To identify novel biomarkers for predicting response to immune checkpoint blockade (ICB) therapy.

Main Methods:

• Analysis of TCGA dataset for PCSK9 association with melanoma.
• In vitro and in vivo studies using murine melanoma B16 cells with PCSK9 gain- and loss-of-function mutants.
• Assessment of intratumoral cholesterol accumulation and RNA sequencing for differential gene expression.
• Identification and validation of gene networks and biomarkers for ICB therapy prediction.

Main Results:

• PCSK9 expression correlated with reduced patient survival and promoted melanoma cell proliferation, migration, and tumor growth.
• PCSK9 induced intratumoral cholesterol accumulation and modulated immune cell infiltration, including T cells and NK cells.
• A subset of PCSK9-associated genes predicted poor prognosis and resistance to ICB therapy.
• Novel biomarkers, including FAS ligand, were identified and used to construct predictive panels for ICB response.

Conclusions:

• Tumor-derived PCSK9 is a critical factor in melanoma pathogenesis, linked to cholesterol accumulation and immune evasion.
• PCSK9 influences the tumor microenvironment and systemic immunity, contributing to melanoma's ability to evade immune surveillance.
• The PCSK9 network yields novel biomarkers that effectively predict patient response to ICB therapies, offering potential for personalized treatment strategies.