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] We utilized PCa stem cells (PCSC), primary and metastatic PCa, intact and castrated Pten mice, TRAMP mice, and xenografts produced in intact and castrated mice using LNCaP cells overexpressing empty vector (EV), PCSK9, gain-of-function (D374Y) and loss-of-function (Q152H) mutant. TRAMP/Pcsk9 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] PCSK9 upregulation occurs in PCSC, intact and castrated prostate-specific Pten mice, primary, metastatic, and castration resistant PCa (CRPC). PCSK9 increased LNCaP tumor growth under intact and castrated conditions, and elevated intratumoral cholesterol, angiogenesis, nuclear AR, CYP17A1, and SRD5A1. Evolocumab treatment extended overall survival (OS) in TRAMP mice. TRAMP;Pcsk9 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.