PCSK9 promotes prostate cancer via facilitating intratumoral cholesterol accumulation and enhancing immunosuppressive tumor microenvironment

INTRODUCTION: Cholesterol plays critical roles in prostate cancer (PCa) proliferation, immune evasion, and androgen signaling. PCSK9 regulates cholesterol metabolism. Its role in PCa remains unclear. OBJECTIVE: To investigate PCSK9's function in promoting PCa progression and the underlying mechanisms. METHODS: mice were generated. The anti-PCSK9 antibody evolocumab was used. Androgen receptor (AR) signaling, angiogenesis, cholesterol accumulation, immune checkpoint (IC) expression, and CD8+ T cell infiltration were examined. RNA-seq was performed on xenografts. Differentially expressed genes and pathway alterations were evaluated. RESULTS: mice exhibited reduced tumor growth, metastasis, intratumoral cholesterol, CYP17A1, SRD5A1, ABI3, CORO1A, VISTA, CD53, enhanced CD8+ T cell infiltration and OS. ABI3, CORO1A, and CD53 are novel to PCa. ABI3 and CORO1A strongly correlate with CD53, VISTA, and multiple other ICs (n = 18) in 8 independent PCa populations, including metastases and CRPCs. ABI3 and CORO1A are among 15 immune-related genes (Sig15IM) upregulated by PCSK9. Sig15IM robustly stratifies PCa recurrence. In multiple single-cell RNA-seq datasets, Sig15IM, ABI3, ABI3corrgenes (ABI3 correlated genes), CORO1A, CORO1Acorrgenes, and CD53 are predominantly expressed or upregulated in exhausted CD8+ T and Treg in PCa and eight other cancer types. CONCLUSIONS: PCSK9 promotes PCa progression via enhancing intratumoral cholesterol accumulation and shaping immunosuppressive microenvironment involving novel immunosuppressive factors: Sig15IM, ABI3, CORO1A, ABI3corrgenes, CORO1Acorrgenes, and CD53. PCSK9 facilitates VISTA expression in PCa.