Research background
Immune checkpoint therapy, particularly anti-PD-1/PD-L1 immunotherapy, have achieved significant results in the treatment of various tumours.
However, most cancer patients show a low response rate to PD-1/PD-L1 blockade, especially those with microsatellite stable/mismatch repair-proficient (MSS/pMMR) colorectal cancer subtypes.
Therefore, there is an urgent need for new approaches to enhance the efficacy of anti-PD-1/PD-L1 immunotherapy.
In recent years, inhibiting PCSK9, a serine proteinase that regulates cholesterol metabolism, has been demonstrated to be a method enhancing the antitumor effects of anti-PD-1/PD-L1 treatment to some extent.
Thus, combining PCSK9 inhibitors with anti-PD-1/PD-L1 immunotherapy may be a new strategy to improve antitumor effects.
Research advances
Proprotein convertases (PCs) are a unique class of serine proteinases.
PCSK9 is the ninth member of the PC family programmed by the gene PCSK9 located on chromosome 1, which plays a role in regulating cholesterol metabolism.
This review outlines the key role of PD-1/PD-L1 in tumour immunity and the potential of PCSK9 inhibitors in enhancing anti-PD-1/PD-L1 immunotherapy.
The article mentions that blocking the PD-1/PD-L1 immune checkpoint can restore T-cell function, but most patients do not respond well.
Cholesterol metabolism plays an important role in tumour development, and PCSK9 inhibition may suppress tumour growth by reducing serum cholesterol levels and enhance the effects of PD-1/PD-L1 blockade.
Figure 1 illustrates the key findings of anti-PD-1/PD-L1 immunotherapy and PCSK9 inhibitors and their combined application in tumour treatment, emphasising the research advance of PCSK9 inhibitors as an emerging enhancer.
Cholesterol, a crucial component of biological membranes and lipid rafts, plays an important role in tumour proliferation and development.
This review summarises three main ways in which cholesterol affects tumour development, including tumorigenic signalling pathways, the tumour microenvironment (TME), and ferroptosis (Figure 2).
Among them, cholesterol exerts its effects by regulating various signalling pathways in tumour cells, including the Hedgehog signalling pathway, Wnt signalling pathway, and the PI3K/AKT signalling pathway, etc.
(Figure 2a).
Cholesterol can also affect the function of immune cells in the TME by upregulating various inhibitory receptors, thereby influencing tumour development (Figure 2b).
Although the role of cholesterol in ferroptosis is not yet clear, intermediate metabolites and enzymes in the cholesterol biosynthesis process, such as isopentyl pyrophosphate (IPP), farnesyl pyrophosphate (FPP), and squalene, have a significant impact on ferroptosis.
This reveals the indirect role of cholesterol in ferroptosis (Figure 2c).
In addition to being regulated by cholesterol metabolism, tumour cells can also alter their own cholesterol metabolism, which is the reprogramming of cholesterol metabolism in tumour cells.
The process facilitates the occurrence and development of cancer.
Specifically, tumour cells meet their demand for cholesterol by enhancing its biosynthesis and uptake.
The key enzymes and signalling pathways involved in this process show significantly increased expression levels in various cancers (Figure 3).
Furthermore, tumour cells can also maintain high cholesterol levels in the tumour microenvironment by regulating cholesterol efflux and esterification.
PCSK9 is a serine protease that primarily binds to the low-density lipoprotein receptor (LDLR) on the cell membrane in the plasma, leading to the internalisation of LDLR and subsequent vesicular transport to lysosomes for degradation.
This process prevents the recycling of LDLR to the cell surface, resulting in reduced cholesterol uptake by cells and increased serum cholesterol levels.
Therefore, PCSK9 inhibitors can reduce the degradation of LDLR and increase its recycling by blocking the binding of PCSK9 to LDLR, thereby lowering serum cholesterol levels, treating atherosclerosis and cardiovascular diseases, and affecting tumour development through various mechanisms (Figure 4).
In addition to regulating cholesterol metabolism, inhibiting PCSK9 can also enhance the antitumor effects of anti-PD-1/PD-L1 immunotherapy through various mechanisms (Figure 5).
The specific mechanisms include:
1. Maintaining the recycling of MHC I: PCSK9 binds to the major histocompatibility protein class I (MHC I), promoting its degradation in lysosomes and reducing the expression of MHC I on the cell surface, thereby weakening the antigen presentation process.
Inhibition of PCSK9 can restore the recycling of MHC I, enhance antigen presentation, and promote T cell recognition and killing of tumour cells.
2. Promoting LDLR-mediated TCR recycling and signalling: LDLR is not only involved in cholesterol metabolism but also in the recycling and signalling of the T cell receptor (TCR).
PCSK9, by binding to LDLR, blocks the interaction between LDLR and TCR, affecting TCR recycling and T cell activation.
Inhibition of PCSK9 can restore TCR recycling and enhance the antitumor activity of T cells.
3. Regulating immune cells in the tumour microenvironment: Inhibition of PCSK9 can affect the infiltration and exclusion of immune cells in the TME, particularly by increasing the infiltration of CD8+ T cells and reducing the number of regulatory T cells (Treg), thereby enhancing the antitumor immune response.
Future perspectives
This article reviews ongoing clinical trials that assess the efficacy and safety of combining PCSK9 inhibitors with anti-PD-1/PD-L1 therapies in various types of cancer, aiming to explore whether the combination of the two treatments can produce synergistic effects, enhance tumour immunogenicity, and overcome resistance to immune checkpoint inhibitors.
The author team has also initiated a multicenter, prospective, randomised controlled study to evaluate the efficacy and safety of neoadjuvant chemoradiotherapy combined with PD-1 inhibitor (sintilimab) and PCSK9 inhibitor (tafolecimab) in the treatment of pMMR/MSS locally advanced rectal cancer (LARC).
Patients are randomly assigned to the control group and the experimental group; the control group receives long-term radiotherapy, capecitabine chemotherapy, and PD-1 inhibitor treatment as neoadjuvant therapy, while the experimental group receives additional PCSK9 inhibitor treatment based on the control group's therapy.
The study hopes that this combined strategy will improve the organ preservation rate and quality of life for LARC patients without affecting survival outcomes, and further explore ways to enhance the therapeutic effects of immune checkpoint therapies in pMMR/MSS patients.
Source: Research