Inhibition of PCSK9: A Promising Enhancer for Anti-PD-1/PD-L1 Immunotherapy

Abstract

Immune checkpoint therapy, such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blockade, has achieved remarkable results in treating various tumors. However, most cancer patients show a low response rate to PD-1/PD-L1 blockade, especially those with microsatellite stable/mismatch repair-proficient colorectal cancer subtypes, which indicates an urgent need for new approaches to augment the efficacy of PD-1/PD-L1 blockade. Cholesterol metabolism, which involves generating multifunctional metabolites and essential membrane components, is also instrumental in tumor development. In recent years, inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine proteinase that regulates cholesterol metabolism, has been demonstrated to be a method enhancing the antitumor effect of PD-1/PD-L1 blockade to some extent. Mechanistically, PCSK9 inhibition can maintain the recycling of major histocompatibility protein class I, promote low-density lipoprotein receptor-mediated T-cell receptor recycling and signaling, and modulate the tumor microenvironment (TME) by affecting the infiltration and exclusion of immune cells. These mechanisms increase the quantity and enhance the antineoplastic effect of cytotoxic T lymphocyte, the main functional immune cells involved in anti-PD-1/PD-L1 immunotherapy, in the TME. Therefore, combining PCSK9 inhibition therapy with anti-PD-1/PD-L1 immunotherapy may provide a novel option for improving antitumor effects and may constitute a promising research direction. This review concentrates on the relationship between PCSK9 and cholesterol metabolism, systematically discusses how PCSK9 inhibition potentiates PD-1/PD-L1 blockade for cancer treatment, and highlights the research directions in this field.

Fig. 1.

Milestone events of PCSK9 inhibitor and anti-PD-1/PD-L1 immunotherapy. The key findings on PCSK9 inhibitor, the major achievements of anti-PD-1/PD-L1 immunotherapy, and their combination were reviewed retrospectively. FDA, Food and Drug Administration; mAb, monoclonal antibody; PCSK9, proprotein convertase subtilisin/kexin type 9; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2. Created with BioRender.com.

Fig. 2.

Role of cholesterol in tumor development. (A) Signaling pathways regulated by cholesterol in tumor cells. Cholesterol performs functions in tumor development via Hedgehog, Wnt, and PI3K/AKT signaling pathways. (B) Cholesterol affects the TME. The up-regulated cholesterol in the TME may cause CD8⁺ T-cell exhaustion via up-regulated expression of immune checkpoints, thereby reducing cytokine secretion. (C) Cholesterol and ferroptosis. Cholesterol indirectly affects ferroptosis via the intermediate metabolites and enzymes during cholesterol biosynthesis. FPP, farnesyl pyrophosphate; GzmB, granzyme B; IFN-γ, interferon-γ; IPP, isopentenyl-pyrophosphate; LAG-3, lymphocyte activation gene-3; PD-1, programmed cell death protein 1; PI3K/AKT, phosphoinositide 3-kinase/protein kinase B; RTK, receptor tyrosine kinase; sec-tRNA, selenocysteine-specific transfer ribonucleic acid; TIM-3, T-cell immunoglobulin domain and mucin domain-3; TME, tumor microenvironment; TNF-α, tumor necrosis factor-α; Wnt, Wingless and Int-1. Created with BioRender.com.

Fig. 3.

Altered cholesterol metabolism in cancer. Cholesterol biosynthesis and uptake are enhanced in tumor cells. These processes are reprogrammed in a direction that favors tumor growth and development. Acetyl-CoA, acetyl coenzyme A; FPP, farnesyl pyrophosphate; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme-A; HMGCR, HMG-CoA reductase; IPP, isopentenyl-pyrophosphate; LDLR, low-density lipoprotein receptor; NPC1L1, Niemann-Pick C1-like1; SQLE, squalene epoxidase; SREBP, sterol regulatory element binding protein. Created with BioRender.com.

Fig. 4.

The biology of PCSK9. The biological structure of PCSK9 (upper left). The physiological role of PCSK9 in cholesterol metabolism. LDLR combines with LDL and transports it from plasma to endosome. After releasing LDL in the endosome, LDLR will recycle to the plasma membrane and continue to transport LDL for degradation. PCSK9 may bind to LDLR and directs it to the lysosome for degradation after LDL release. The process can be blocked if a PCSK9 inhibitor combines with PCSK9 (upper right and lower right). PCSK9 promotes tumorigenesis. Corresponding to the effects of cholesterol on tumor growth, PCSK9 may indirectly promote tumorigenesis by up-regulating the tumorigenic signaling pathway, resisting ferroptosis, and affecting the TME (lower left). CAP1, cyclase-associated protein 1; CHRD, C-terminal Cys/His-rich domain; LDLR, low-density lipoprotein receptor; MHC I, major histocompatibility protein class I; PCSK9, proprotein convertase subtilisin/kexin type 9; PD-1, programmed cell death protein 1. Created with BioRender.com.

Fig. 5.

PCSK9 prevents MHC I and LDLR-mediated TCR recycling. PCSK9 binds to MHC I and directs it to the lysosomal pathway for degradation instead of being recycled back to the cell surface. PCSK9 can also interfere with TCR recycling and signaling by binding to LDLR and preventing its interaction with TCR. By blocking the LDLR–TCR interaction, PCSK9 causes TCR to be sorted into the lysosomal pathway instead of being recycled back to the cell surface. The PCSK9 inhibitor may block these processes. CTL, cytotoxic T lymphocyte; ER, endoplasmic reticulum; LDLR, low-density lipoprotein receptor; MHC I, major histocompatibility protein class I; PCSK9, proprotein convertase subtilisin/kexin type 9; TCR, T-cell receptor. Created with BioRender.com.