Next Article in Journal
From Localized Mild Hyperthermia to Improved Tumor Oxygenation: Physiological Mechanisms Critically Involved in Oncologic Thermo-Radio-Immunotherapy
Previous Article in Journal
Dose Distribution of High Dose-Rate and Low Dose-Rate Prostate Brachytherapy at Different Intervals—Impact of a Hydrogel Spacer and Prostate Volume
Previous Article in Special Issue
Modulation of Plasma Lipidomic Profiles in Metastatic Castration-Resistant Prostate Cancer by Simvastatin
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 15
Issue 5
10.3390/cancers15051397
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology

by
Vincenzo Quagliariello
1,*,
Irma Bisceglia
2,
Massimiliano Berretta
3,
Martina Iovine
1,*,
Maria Laura Canale
4,
Carlo Maurea
5,
Vienna Giordano
1,
Andrea Paccone
1,
Alessandro Inno
6 and
Nicola Maurea
1
1
Division of Cardiology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Napoli, Italy
2
Servizi Cardiologici Integrati, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, 00152 Roma, Italy
3
Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy
4
U.O.C. Cardiology Department, Ospedale Versilia, Lido di Camaiore (LU), 55049 Camaiore, Italy
5
Department of Neurology, University of Salerno, 84084 Fisciano, Italy
6
Medical Oncology Department, IRCCS Ospedale Sacro Cuore Don Calabria, 37024 Negrar di Valpolicella, Italy
*
Authors to whom correspondence should be addressed.
Cancers 2023, 15(5), 1397; https://doi.org/10.3390/cancers15051397
Submission received: 27 January 2023 / Revised: 17 February 2023 / Accepted: 20 February 2023 / Published: 22 February 2023
(This article belongs to the Special Issue The Pivotal Role of Lipids in Cancer Pathophysiology, Diagnosis and Therapy)
Browse Figures
Review Reports Versions Notes

Abstract

:

Simple Summary

Atherosclerosis is a critical cardiovascular disease associated with the use of immune checkpoint inhibitors (ICIs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key orchestrator of atherosclerotic process and it is also involved in cancer progression and immune-resistance. In this context, data from recent meta-analysis and cardiovascular outcome trials associate PCSK9 levels to reduced ICIs-related cancer responsiveness and to high risk of atherosclerotic cardiovascular diseases. This review summarizes the pleiotropic effects of PCSK9 in heart failure, atherosclerosis, and cancer immune recognition, and outlines its ability to represent a new pharmacological target in patients who develop ICIs-related atherosclerosis to reduce cardiovascular mortality and to improve overall survival.

Abstract

Cancer patients treated with immune checkpoint inhibitors (ICIs) are exposed to a high risk of atherosclerosis and cardiometabolic diseases due to systemic inflammatory conditions and immune-related atheroma destabilization. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein involved in metabolism of low-density lipoprotein (LDL) cholesterol. PCSK9 blocking agents are clinically available and involve monoclonal antibodies, and SiRNA reduces LDL levels in high-risk patients and atherosclerotic cardiovascular disease events in multiple patient cohorts. Moreover, PCSK9 induces peripheral immune tolerance (inhibition of cancer cell- immune recognition), reduces cardiac mitochondrial metabolism, and enhances cancer cell survival. The present review summarizes the potential benefits of PCSK9 inhibition through selective blocking antibodies and siRNA in patients with cancer, especially in those treated with ICIs therapies, in order to reduce atherosclerotic cardiovascular events and potentially improve ICIs-related anticancer functions.

1. Introduction

Immune checkpoint inhibitors (ICIs) are increasingly used in oncology to treat multiple malignancies, including melanoma, non-small cell lung cancer, metastatic breast cancer, and others [1,2]. In most cases, ICIs are monoclonal antibody antagonists of programmed death-ligand 1 (PDL-1) or programmed cell death protein 1 (PD-1) or cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) which are the main drivers of peripheral immune tolerance, even towards tumors [3,4]. Briefly, ICIs antagonize the inhibition of lymphocyte uptake against tumors, resulting in a lymphocyte-mediated anticancer effect [4]. Recent trials associate ICIs with radiotherapy [5], standard chemotherapy (anthracyclines or platinum-based anticancer drugs) [6,7], targeted therapies (HER-2 blocking agents, TKi and others) [8], and combination therapies (i.e., PD-1 and CTLA-4 blocking agents) [9,10]. In brief, combination therapies involving ICIs and standard chemotherapies increase lymphocytic infiltration in neoplastic tissue in a pro-inflammatory microenvironment, which make CD56+ and CD3− large granular lymphocytes more reactive against tumor cells [11,12]. However, ICIs therapies are associated with a broad spectrum of endocrine diseases and, albeit, relatively rare cardiovascular side effects [13,14], including myocarditis [15], vasculitis [16], inflammatory endocrinopathies [17], mucositis [18], and arthritis [19]. The main mechanisms of cardiotoxicity are not deeply understood, but NLRP-3/IL-1overexpression, My-D88/TLR4, and cytokine-mediated pathways are still considered to be key orchestrators [20,21] in ICIs-mediated side effects in preclinical and clinical models [21]. Very recently, atherosclerosis has emerged as a new considerable ICI-s mediated side effect in cancer patients [22,23]. Briefly, exposure to PD-1 or PDL-1 or CTLA-4 blocking agents increases VCAM-1 and ICAM-1 expression in luminal membrane of vascular endotheliocytes, thus stimulating IL-1, IL-6, and TNF-α levels associated with instability of the atherosclerotic plaque. Interleukins 1 and 6 and TNF-α induce LDL uptake and their oxidation to OX-LDL in endothelial cells [24,25,26] (Figure 1).
A new key driver of the atherosclerosis process is proprotein convertase subtilisin/kexin type 9 (PCSK9) [27]. Briefly, PCSK9 is a protein with key roles in hepatic low density lipoprotein (LDL) homeostasis, reducing the LDL-receptor density in hepatocytes [28]. When PCSK9 binds LDL receptors, it prevents the correct recycling on the cell membrane after the natural bond with LDL particles. This effect increases plasma LDL levels and its associated cardiovascular risk [29]. PCSK9 inhibitors (antibody-based blocking agents and miRNAs) are currently used in clinical practice to reduce LDL levels in high risk cardiovascular patients, intolerant to statins, in order to reduce cardiac risk [30]. However, extrahepatic functions of PCSK9 are increasingly studied in the last three years, involving cardiomyocyte [31], endotheliocyte [32], macrophage, and cancer cell metabolism [33], shedding light on possible therapeutic uses of PCSK9 inhibitors to new off-label clinical applications in cardio-oncology. This review assesses the current knowledge about how PCSK9 interacts with the immune environment in cancer tissue and how PCSK9 inhibitors could be beneficial in patients treated with ICIs in primary prevention of atherosclerosis. First, we describe how PCSK9 is involved in cancer progression and immune escape. Then, we review current knowledge on how PCSK9 inhibitors reduce atherosclerosis initiation and progression in patients without cancer and the main molecular pathways involved.

2. ICIs Therapy, PCSK9, and Risk of Atherosclerotic Cardiovascular Diseases

2.1. ICIs-Mediated Atherosclerosis

The use of ICIs can change the peripheral immune tolerance in different tissues, exposing patients to neuro-inflammatory diseases, visceral obesity, atherosclerosis, and leptin resistance [34]. Preclinical models with deactivating mutations of PD-1 or PDL-1 or CTLA-4 genes are more exposed to atherosclerotic plaques characterized by high levels of VCAL-1, ICAM-1, galectine-3, oxLDL, high macrophage density, and pro-inflammatory cytokines [35,36]. In brief, the lack of these immune repressor proteins increases atherogenic phenotype mediated by a high uptake of CD3+/CD4+ lymphocytes and CD3+/CD8+ lymphocytes in atherosclerotic plaque [37]. These findings led to the hypothesis that ICIs could increase the risk of atherosclerotic cardiovascular diseases (ASCD) in cancer patients [38] (Figure 1). Recent clinical studies have confirmed this hypothesis: patients treated with ICIs for two years have a three times higher risk of developing atherosclerosis compared to other therapies [39]. There are additional observational studies associated with the high risk of unstable atherogenic plaques in cancer patients treated with ICIs compared to the general population [40]. However, more in-depth studies should be performed to clarify if combinatorial anti-PD-1 and CTLA-4 therapies could affect the ASCD risk more than a monotherapy regimen.

2.2. PCSK9 Role in Atherosclerotic Pathogenesis

A close correlation between atherosclerosis and PCSK9 has also been observed [41]. In a recent meta-analysis [42], eleven studies in patients with CVD were analyzed. Notably, patients with established CVD and high PCSK9 levels had a 52% higher risk of future total cardiovascular events than those with low PCSK9 concentrations. Patients with high levels of PCSK9 experienced more than 20% of cardiovascular events compared to low levels [43]. Mechanistically, PCSK9 plays a key role in platelet aggregation and adherence to endothelial cells, endothelial dysfunctions, and atherosclerosis [44]. Genetic studies associated loss of function mutation in PCSK9 gene with high LDL levels and high rates of heart failure [45]. Other studies associated high serum PCSK9 levels to a more necrotic core of coronary atherosclerosis independently from LDL levels [46]. These data indicate extra hepatic roles of PCSK9 that do not involve cholesterol homeostasis. However, Vlachopoulos et al. do not associate PCSK9 levels to cardiovascular events in high-risk patients; they only do so in the general population [47]. Additionally, other research groups associated high PCSK9 levels to patients with stable CVD, but not in patients with ACS [48]. However, there are several other associations between PCSK9 and cardiovascular diseases. First, during myocardial infarction, PCSK9 serum levels are upregulated due to pro-inflammatory processes [49]. Moreover, other studies demonstrated that circulating PCSK9 levels rapidly rise after the initiation of statin therapy [50], and there is a sustained increase throughout statin use. Furthermore, it has recently been observed that PCSK9 could reduce the efficacy of statin treatment in patients with high cardiovascular risk, by reducing the LDL receptor density on hepatocytes [51]. Furthermore, a recent gender study concluded that white people and Asian people have variants in the PCSK9 gene that may or may not be associated with different LDL concentrations [52]. The main cardiovascular outcomes trials, which will be discussed in the next paragraph, called Evaluation of Cardiovascular Outcomes After an ACS During Treatment With Alirocumab (ODYSSEY) [53] and Further CV Outcomes Research with PCSK9 Inhibition In subjects With Elevated Risk (FOURIER) [54], analyzed cardiovascular benefits of PCSK9 inhibitors in non-cancer patients, and recruited mostly only white patients. Being a minority in the makeup made up of ascitic patients, it is probable that the effects of PCSK9 inhibitors in white people are not the same due to variations in the genetic profile of different races [54].

2.3. PCSK9 in Cardiomyocyte and Endothelial Metabolism

The PCSK9 gene is located on chromosome 1p32.3 that is expressed in several organs, including the liver, kidneys, small intestine, heart, and cancer cells [55]. The encoded protein is of 692 aminoacids, characterized by three domains: signal domain, pro-domain, and V domain (Figure 2). Interestingly, the key process for maturation and secretion of active PCSK9 is secondary to the cleavage of pro-domain in the S 38 and P47 region [56]. The first clinical evidence on the association between PCSK9 and CV events are based on loss of function or gain of function in PCSK9 gene: patients with gain of function mutations of PCSK9 gene experienced high levels of serum LDL-C, a reduction in LDL receptor levels on hepatocytes (by more than 35%), and premature cardiovascular events compared to non-mutated patients [57]. Contrary, loss of function mutations are associated with low serum levels of PCSK9 and more than 40% reduction of LDL-C with consequent risk reduction in incidences of ischemic heart diseases [57]. PCSK9 is also expressed in cardiomyocytes [58]. Very recent studies described PCSK9 functions in cardiomyocyte autophagy, pyroptosis, ferroptosis, and apoptosis [58]. Detrimental events such as hypoxia, acute inflammation, and heart failure can induce different types of cardiomyocyte cell death through PCSK9 overexpression [59]. Specifically, high cholesterol and insulin levels induce overexpression of PCSK9, which activates DRP-1 in mitochondria triggering autophagy [60]. Moreover, PCSK9 exacerbates mitochondrial ROS production, resulting in the activation of the LKB1-AMPK pathway [61]. Moreover, in cases of OX-LDL intake in the cardiomyocyte, PCSK9 overexpression causes mitochondrial DNA damage, resulting in the activation of NLRP3 inflammasome/Caspase-1/Interleukin-1 pathway [62]. This process activates cardiomyocyte pyroptosis. Increased serum levels of IL-1 and IL-6 directly result in PCSK9 overexpression, which also induces cardiomyocyte apoptosis via caspase-9 and 3 [63]. Another biochemical mechanism of PCSK9 cardiac and endothelial toxicity is mediated by lipid peroxides [64]. Lipid peroxidation, which can be induced by acute inflammation, smoking, and some chemotherapeutic drugs such as anthracyclines, leads to the formation of MDA and 4-HNA by the Fenton reaction [65,66]. PCSK9 activates the Fenton reaction, whose gene expression is activated by the over-intake of Fe3+ in cardiomyocytes and endotheliocytes [66]. Furthermore, intracellular overexpression of PCSK9 results in decreased FFA uptake and utilization through a specific mechanism: PCSK9 competes with FFAs for binding to the CD36/FAT receptor and reduces their membrane recycling, resulting in an increase in systemic FFA levels and a significant reduction in fatty acid beta oxidation and the Krebs cycle [67]; this is the primary driver of atherosclerosis and cardiomyocyte injury processes. Moreover, it is conceivable that PCSK9 has a role in heart failure, hypertrophy, and cardiac fibrosis. These effects could be mediated by TNF-a and some chemokines; in fact, TNF-a upregulates PCSK9 gene expression via Peroxisome proliferator-activated receptors (PPARs) and PPAR gamma coactivator-1a (PGC1) pathways [68].

3. PCSK9i in Cardiovascular Outcome Trials

Current guidelines of the American College of Cardiology and American Heart Association recommend the addition of non-statin cholesterol-lowering therapies for patients at very high risk of major adverse cardiovascular events (MACE) when LDL-C levels remain ≥ 70 mg/dL [69]. About half of coronary heart disease patients on moderate- or high-dose statin therapies reduce LDL-C less than 70 mg/dL [70]. In this category of patients, there could be an additional clinical benefit deriving from the addition or substitution with other cholesterol-lowering agents, such as PCSK9 inhibitors, and this is a point of discussion in cardiology. Some randomized clinical trials have demonstrated how the administration of PCSK9 inhibitors, evolocumab, alirocumab, bococizumab, or inclisirian, as monotherapy or in combination with statins can reduce systemic levels of atherogenic and pro-inflammatory lipoproteins [71,72]. Notably, PCSK9i significantly reduces LDL-C and up to 25% lipoprotein a (Lpa) [73]. Effects on LPa levels are of particular interest in cardiology, considering its well established strong atherogenic, pro-inflammatory, and pro-thrombotic effects [74]. A recent trial concluded that among patients with advanced stable coronary artery disease, Lp(a) is associated with accelerated progression of coronary low-attenuation plaque (necrotic core) [75]. This may explain the association between Lp(a) and the high residual risk of myocardial infarction, providing support for Lp(a) as a treatment target in atherosclerosis [76]. The most known CVOT including PCSK9i are the FOURIER and ODYSSEY Outcomes trials. Patients with established cardiovascular disease or acute coronary syndrome (ACS) and elevated levels of LDL-C, non–high-density lipoprotein cholesterol, or apolipoprotein B were enrolled in these studies [77]. Patients treated with PCSK9i reduced MACE, coronary heart disease, peripheral artery disease, and venous thromboembolic events. Some of these beneficial effects were also associated with LPa reductions [78]. A brief description of the clinical benefits of each PCSK9i is provided below and summarized in Table 1:
-
Evolocumab
Patients treated with evolocumab halved LDL cholesterol values [79]. Furthermore, a recent meta-analysis showed that patients treated with evolocumab also had a slight but significant increase in HDL cholesterol; on the other hand, total cholesterol levels decreased by about 35–37% but with great heterogeneity of age and sex [80]. Evolocumab was not effective in reducing triglyceride levels. Regarding adverse cardiac events, a recent meta-analysis showed that evolocumab reduced myocardial infarction by 27% and stroke by approximately 21% [81]. A further interesting finding concerns unstable angina requiring revascularization which was reduced by 16% in patients treated with evolocumab vs. placebo. A further recent meta-analysis showed that evolocumab treatment reduces composite or CV death, myocardial infarction, stroke, and unstable angina by 15%. Moreover, in HUYGENS (High-Resolution Assessment of Coronary Plaques in a Global Evolocumab Randomized Study) study [82], evolocumab administration stabilized coronary plaque, resulting in regression of atheroma volume in patients with ACS.
-
Alirocumab
Alirocumab is an additional PCSK9 inhibitor that has been extensively studied in cardiovascular outcome trials [83]. A recent meta-analysis showed that patients treated with alorocumab increased HDL cholesterol levels by approximately 5% [84]. Similarly to evolocumab, alirocumab reduces total cholesterol levels without affecting triglyceride levels. Furthermore, alirocumab, similarly to evolocumab, reduced composite of MI, stroke, unstable angina, and CV death. In a biweekly administered regimen, Alirocumab lower LDL-C by 45 to 60% depending on the applied dose (75 mg vs. 150 mg) and by ~ 50% while given monthly in a 300-mg dose [85]. Moreover, we now have evidence that evolocumab and alirocumab treatment, on top of statins, in patients with ACS modifies coronary plaque properties, leading not only to a significant thickening of the fibrous cap, thereby stabilizing it, but also resulting in regression of atheroma volume in PACMAN-AMI (Effects of the PCSK9 Antibody Alirocumab on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction) study [86].
-
Bococizumab
Bococizumab is an additional PCSK9 blocking monoclonal antibody which, unlike the other antibodies, has shown beneficial effects on MACE only in high-risk patients [87]. Two large studies called SPIRE I [88] and II [89] enrolled more than 27,000 low-risk and high-risk patients (LDL 70 and 100 mg/dl, respectively) treated with bococizumab (150mg) twice a week. In SPIRE I [88], bococizumab showed no significant effects on composite of myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, and cardiovascular death. IN SPIRE II, [89] however, bococizumab reduced the primary endpoint of the SPIRE studies by 11%. However, a serious problem occurred in these patients, namely the production of antibodies to bococizumab, which resulted in very frequent injection site adverse reactions [90].
-
Inclisiran
Inclisiran is a novel, small, interfering RNA aimed to target PCSK9 [91]. In detail, the molecule is a modified double-stranded RNA conjugated to triantennary N-acetylgalactosamine (GalNAc). Liver cells are rich in the asialoglycoprotein receptor that binds to GalNAc, therefore, after subcutaneous administration, inclisiran accumulates significantly in the liver [92]. Inclisiran lowered PCSK9 and LDL-C levels in a dose-dependent manner [93]. After 2 doses of inclisiran, LDL-C was reduced by up to 53% at day 180 [94]. Three large, randomized trials evaluated the cardiovascular efficacy of incisiran; these were called ORION 9–10 and 11 trials [95,96]. In the ORION-9 trial, HeFH patients halved LDL cholesterol after approximately 500 days of treatment with inclisirian. In ORION 10 and 11, LDL cholesterol levels were reduced by approximately 52 and 49% over 500 days of treatment with inclisirian. Furthermore, in all trials, inclisirian also significantly reduced levels of total cholesterol, apolipoprotein B, triglycerides, and lipoprotein (a), thereby reducing many cardiovascular risk factors [97]. Another cardiovascular outcome trial, currently underway, called ORION-4 (NCT03705234) [98], recruited 15,000 patients with ASCVD treated with inclisirian (300 mg) administered as a SC injection at randomization, (3 months and then every 6 months) or placebo aimed to evaluate any reductions in coronary heart disease (CHD) death; these were myocardial infarction, fatal or non-fatal ischemic stroke, or urgent coronary revascularization procedures [98].
Table
Table 1. Main cardiovascular benefits derived from PCSK9i therapies in randomized controlled trials.
Table 1. Main cardiovascular benefits derived from PCSK9i therapies in randomized controlled trials.
DrugChemistryCardiovascular BenefitsReferences
EvolocumabAntibody
-
50% reduction in LDL levels
[79]
-
35–37% reduction in total cholesterol; increases in HDL levels
-
27% reduction of myocardial infarction; 21% reduction of stroke
-
15% reduction in composite or CV death, myocardial infarction, stroke, and unstable angina events
-
Stabilization of coronary plaque in patients with ACS
[80]
[81]
[81]
[82]
[83]
AlirocumabAntibody
-
5% increase in HDL levels
-
45/60% reduction in LDL levels
-
Reduction in composite of MI, stroke, unstable angina, and CV death
-
Stabilization of atherosclerotic plaque and regression of atheroma volume in patients with MI
[84]
[85]
[85]
[86]
BococizumabAntibody
-
No significant effects on composite of MI, stroke, hospitalization for unstable angina requiring urgent revascularization, and cardiovascular death
[88]
-
11% reduction in composite of MI, stroke, hospitalization for unstable angina requiring urgent revascularization, and cardiovascular death
[89]
InclisiransiRNA
-
53% reduction in LDL levels
[94]
-
52 and 49% reduction in LDL levels
-
Significant reduction of total cholesterol, Apolipoprotein-B, Triglycerides, and Lipoprotein (a)
[95,96]
[97]

4. PCSK9i in Oncology: Mechanisms and Potential Application

Inhibitors of PCSK9 have been approved for the treatment of atherosclerotic cardiovascular diseases associated with hypercholesterolemia, however, a central role on immune tolerance in oncology has recently been investigated [99]. Mechanistically, PCSK9 inhibits the recycling of major histocompatibility complex type I (MHCI) to the cell surface by promoting MHC I degradation (Figure 3) [100]. The inhibition of PCSK9 increases the expression of MHC I on the tumor cell surface, promoting intratumoral infiltration of cytotoxic lymphocytes [101]. To be more detailed, PCSK9 directly interacts with amyloid precursor-like protein 2 (APLP2) which literally bridges MHC-I towards lysosomal degradation [102]. All of this blocks MHC-I recycling by inducing peripheral immune tolerance. The same mechanism of promotion of lysosomal degradation by MHC-1 occurs for CD81, CD36, and the LDL receptor [103]. Consequently, the use of PCSK9i can didactically create peripheral immune tolerance against tumor cells by optimizing recognition by T lymphocytes [104]. Furthermore, the reduction of plasma levels of total cholesterol would lead to the inhibition of the ACAT-1 enzyme (deputy for cholesterol esterification) with further enhancement of the antitumor immune response [105].
These data reveal that PCSK9 may be a crucial regulator for cancer immunotherapy. Inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase are the most important and studied pharmacological treatments aimed to decrease total cholesterol and LDL [106]. For every 38.6 mg/dl reduction in LDL-C, ASCVD events are reduced by 21% after 1 year of treatment with moderate- or high-intensity statin therapy. Recent RCTs have demonstrated that statin therapy combined with either ezetimibe or PCSK9 inhibitors reduces ASCVD events in high-risk populations [107]. As described in introduction, treatment with ICIs reduce cancer-induced immune tolerance, providing significant improvements in survival and prognosis of cancer patients at different stages of the disease [108]. PCSK9 is a new key player of cancer immune tolerance [109,110,111]. Recently, it was demonstrated that PCSK9 regulates proliferation and apoptosis in human cancer cells [112]. For example, in neuroglioma and NSCLC, knockdown of PCSK9 gene activates cancer apoptosis through caspase-3 and XIAP/p-Akt pathways [113]. Another preclinical study in melanoma-bearing mice concluded that PCSK9 gene silencing significantly increases the response to ICIs [114,115]. PCSK9 is also expressed and released by cancer cells [116,117]. It was also reported that lowering blood cholesterol levels could boost cancer immunotherapy based on adoptive T cells [118]. Cholesterol regulates the recycling of MHC I in cell membrane [119]. PCSK9 blocking agents reduce systemic levels of total cholesterol and LDL, affecting the risk of atherosclerosis but also reducing the supply of cholesterol by cancer cells [120,121] through the enhancement of apolipoprotein E receptor, CD36, β-secretase 1, and others [122,123]. A study on colon cancer [124] reveals that PCSK9 expression is upregulated in tumor cells compared with non-tumor cells and correlates with the degree of tumor invasiveness. Downregulation of the PCSK9 gene reduces colonic epithelial-to-mesenchymal transition, n-cadherin, and type 9 metalloproteases via the PI3K/AKT pathway. Furthermore, PCSK9 regulates the polarization of colonic peritumor macrophages, resulting in a pro-inflammatory and pro-metastatic phenotype [124]. PCSK9 blocking agents could therefore be studied in patients with metastatic colon cancer.
An association study of 14 lobular or ductal breast cancer patients found that systemic levels of PCSK9 are significantly higher in the advanced stage (stage III) than in patients with less aggressive disease stages and in benign lesions (p < 0.05). However, this study involved only a few dozen patients, so studies on a larger cohort of breast cancer patients should be conducted soon [125]. A study of colon-bearing mice treated with PD-1 blocking agents found that treatment with immunotherapy increased tissue expression and systemic levels of PCSK9, CD36, and TGF-β [126]. Combination of PCSK9 and PD-1 blocking agents in these models significantly increased the antitumor efficacy with strong synergism compared to monotherapies [126]. The use of PCSK9 blocking agents increased the levels of pro-inflammatory and immune-stimulant cytokines, of intra-tumoral CD3+CD8+ lymphocytes, reducing CD4+, FOXP3+, CD25+ lymphocyte density. In liver cancer models, researchers [127] demonstrated that PCSK9 is involved in resistance to VEGFR, PDGFR, and RAF kinases inhibitor sorafenib by direct inhibition of phosphatase and tensin homolog (PTEN) and consequent upregulation of the AKT pathway. In another study in colorectal cancel model, [128,129] authors founded that PCSK9 induces oncogenesis in APC/KRAS mutant models of colon cancer and that systemic PCSK9 levels correlate with reduced survival in this patient cohort. PCSK9 blocking agents, especially when combined with statins, inhibit the neoplastic growth of APC/KRAS mutant colon cancer xenograft models by suppressing the KRAS/MEK/ERK pathway. Thus, the investigators conclude that PCSK9 inhibition may be a valid adjuvant therapy for APC/KRAS mutant colorectal cancer by suppression of the KRAS/MEK/ERK oncogenic pathway. A recent review [130] summarizes that PCSK9 blocking agents are able to reduce prostate, lung, colon, and glioblastoma cancer cell growth through the induction of apoptosis, pyroptosis, and necrosis. Moreover, PCSK9 gene silencing reduces liver metastasis in melanoma-bearing mice through induction of intra-tumoral CD3+CD8+ lymphocytes levels [131]. In another recent meta-analysis, patients with PCSK9 loss of function mutation have a lower odds of prostate cancer compared to non-mutant PCSK9 subjects [132]. Another study on ovarian cancer models [133], evidenced that PCSK9 is also upregulated in ovarian cancer cells and correlated with tumor invasiveness by direct stimulation of ERK/MEK pathways. The use of PCSK9 blocking monoclonal antibodies or SiRNAs suppresses the growth of ovarian cancer cells by reducing AKT phosphorylation by reducing endogenous lipogenesis in these cells [133].
A clinical study of non-small cell lung cancer patients has shown that low systemic levels of PCSK9 (<95 ng/mL) predict better responsiveness to the Programmed Death-1 (PD-1) Inhibitor Nivolumab and have better overall survival than patients with higher blood levels (>120 ng/mL) [134]. In a recent biochemical study [135], an aptamer PL1 and Pcsk9 siRNA were able to potentiate anti PD-1/PD-L1 therapies in human colorectal cancer cells through enhancement of IFN-γ and Granzyme B expression. A preclinical research study concluded that PCSK9 inhibition is able to increase major histocompatibility protein class I (MHC-I) membrane density on different cancer cells through the inhibition MHC-I lysosomal degradation, thereby increasing the concentration of intratumoral cytotoxic CD3+ CD8+ lymphocytes [136].

5. PCSK9 Inhibitors in Cardio-Oncology: A Potential Therapy in ASCVD Cancer Patients Treated with ICIs

Immune-related adverse events (irAEs) seen in cancer patients treated with ICIs includes myocarditis, myositis, myasthenia gravis–like syndrome, endocrinophaties, and visceral obesity [137,138]. Moreover, immune-related atherosclerotic vascular events (irAVEs) are also still associated with ICIs therapy in preclinical and clinical trials. In a recently published retrospective study, ICIs therapies increased atherosclerotic plaques volume through the involvement of immune-related inflammation pathways. Other ongoing prospective studies (NCT04586894, NCT03709771, NCT04115410) are aimed to demonstrate if ICIs therapies could increase AVEs events and potential mechanisms involved [139,140,141]. However, in cardio-oncology, the reduction of several cardiovascular and cancer risk factors should be strictly considered. Among the best known cardio-oncological risk factors, we have the reduction of hyperglycemia, hypercholesterolemia, especially OX-LDL, triglycerides, homocysteine, insulin levels, hs-CRP, visceral fat, and smoking. Based on this, patients should be encouraged to follow a diet that complies with the European anti-cancer code and the WCRF directives, a non-sedentary lifestyle where possible (which is difficult especially in metastatic patients), and avoid smoking. However, PCSK9i-based drugs could be key cardioprotective strategies to reduce ASCVD in cancer patients treated with ICIs. Based on this, it is conceivable that a target population that could benefit from PCSK9 therapy are cancer patients treated with ICIs therapies, especially those with confirmed ASCVD. To this end, therefore, the benefits would be multiple: 1. enhancement of immunotherapy efficacy; 2. inhibition of mechanisms of resistance to apoptosis; 3. reduction of the risk of destabilization of stenotic plaque; 4. reduction of the risk of atherosclerosis induced by ICIs. To date, no studies have evaluated if PCSK9 blocking agents could reduce ASCVD in cancer patients treated with ICIs. A potential clinical trial could therefore include patients treated with ICIs in monotherapy or in combination with, for example, Ipilimumab, Nivolumab, Pembrolizumab, Durvalumab, Avelumab, or Atezolizumab.

6. Conclusions

Inhibition of PCSK9 has emerged as a novel therapy to treat hypercholesterolemia and related cardiovascular diseases. Recent preclinical and clinical evidence supports the anticancer and immune-stimulating properties of PCSK9 inhibition therapy through the inhibition of peritumoral peripheral immune tolerance and reduction of cytokines involved in cancer cell survival. Cancer patients treated with ICIs in monotherapy or in an association therapy regimen have a three times greater risk of developing atherosclerotic plaques than patients not treated with ICIs and represent a population category that requires close pharmacological monitoring of atherosclerotic risk factors, including systemic inflammation, LDL, and OX-LDL levels. Cancer patients who develop ICIs-related ASCVD could benefit from PCSK9 inhibition therapy in order to reduce atherosclerotic events, cardiovascular mortality, and improve overall survival. Therefore, cardioprotective properties of PCSK9 inhibitors should be urgently explored in randomized clinical trials in patients with cancer at high risk of ASCVD.

Author Contributions

Conceptualization, V.Q. and N.M.; methodology, V.Q.; software, V.Q.; validation, N.M., A.I. and M.L.C.; formal analysis, M.I. and V.G.; investigation, C.M. and M.B.; resources, N.M.; data curation, M.L.C. and I.B.; writing—original draft preparation, V.Q.; writing—review and editing, V.Q. and N.M.; visualization, A.I.; supervision, N.M. and A.P.; project administration, M.I.; funding acquisition, N.M. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Italian Ministry of Health Ricerca Corrente funds, titled “Cardiotossicità da chemioterapie, targeted therapies e immunoterapie, diagnosi precoce e cardioprotezione. Ricerca preclinica e clinica” (Linea 6/1).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Tan, S.; Day, D.; Nicholls, S.J.; Segelov, E. Immune Checkpoint Inhibitor Therapy in Oncology: Current Uses and Future Directions: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022, 4, 579–597. [Google Scholar] [CrossRef]
  2. Li, H.; Zhao, A.; Li, M.; Shi, L.; Han, Q.; Hou, Z. Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy. Front. Immunol. 2022, 13, 1046755. [Google Scholar] [CrossRef] [PubMed]
  3. Yu, Z.; Vyungura, O.; Zhao, Y. Molecular subtyping and IMScore based on immune-related pathways, oncogenic pathways, and DNA damage repair pathways for guiding immunotherapy in hepatocellular carcinoma patients. J. Gastrointest. Oncol. 2022, 13, 3135–3153. [Google Scholar] [CrossRef] [PubMed]
  4. Lorentzen, C.L.; Haanen, J.B.; Met, Ö.; Svane, I.M. Clinical advances and ongoing trials on mRNA vaccines for cancer treatment. Lancet Oncol. 2022, 23, e450–e458, Erratum in Lancet Oncol. 2022, 23, e492. [Google Scholar] [CrossRef]
  5. Xu, H.; Cao, D.; Zhou, D.; He, A.; Ge, W.; Xu, X. Assessing Potential Factors Influencing the Efficacy of Immune Checkpoint Inhibitors with Radiation in Advanced Non-Small-Cell Lung Cancer Patients: A Systematic Review and Meta-Analysis. J. Oncol. 2023, 2023, 4477263. [Google Scholar] [CrossRef]
  6. Røssevold, A.H.; Andresen, N.K.; Bjerre, C.A.; Gilje, B.; Jakobsen, E.H.; Raj, S.X.; Falk, R.S.; Russnes, H.G.; Jahr, T.; Mathiesen, R.R.; et al. Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: The randomized, double-blind phase 2b ALICE trial. Nat. Med. 2022, 28, 2573–2583. [Google Scholar] [CrossRef]
  7. Tao, Y.; Biau, J.; Sun, X.; Sire, C.; Martin, L.; Alfonsi, M.; Prevost, J.; Modesto, A.; Lafond, C.; Tourani, J.; et al. Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): A multicenter, randomized, phase II trial. Ann. Oncol. 2023, 34, 101–110. [Google Scholar] [CrossRef]
  8. Padmanabhan, R.; Kheraldine, H.; Gupta, I.; Meskin, N.; Hamad, A.; Vranic, S.; Al Moustafa, A.-E. Quantification of the growth suppression of HER2+ breast cancer colonies under the effect of trastuzumab and PD-1/PD-L1 inhibitor. Front. Oncol. 2022, 12, 977664. [Google Scholar] [CrossRef]
  9. Basudan, A.M. The Role of Immune Checkpoint Inhibitors in Cancer Therapy. Clin. Pract. 2022, 13, 22–40. [Google Scholar] [CrossRef]
  10. Versluis, J.; Menzies, A.; Sikorska, K.; Rozeman, E.; Saw, R.; van Houdt, W.; Eriksson, H.; Klop, W.; Ch’Ng, S.; van Thienen, J.; et al. Survival Update of Neoadjuvant Ipilimumab Plus Nivolumab in Macroscopic Stage III Melanoma in the OpACIN and OpACIN-Neo Trials. Ann. Oncol. 2023; ahead of print. [Google Scholar] [CrossRef]
  11. Xu, Y.; Hao, X.; Ren, Y.; Xu, Q.; Liu, X.; Song, S.; Wang, Y. Research progress of abnormal lactate metabolism and lactate modification in immunotherapy of hepatocellular carcinoma. Front. Oncol. 2023, 12, 1063423. [Google Scholar] [CrossRef] [PubMed]
  12. Pandey, P.; Khan, F.; Upadhyay, T.K.; Maqsood, R. Review to Understand the Crosstalk between Immunotherapy and Tumor Metabolism. Molecules 2023, 28, 862. [Google Scholar] [CrossRef] [PubMed]
  13. Thavendiranathan, P.; Sacher, A. A New Risk Factor for Cardiovascular Events in Patients Receiving Immune Checkpoint Inhibitor Therapy? JACC CardioOncol. 2022, 4, 670–672. [Google Scholar] [CrossRef]
  14. Quinaglia, T.; Gongora, C.; Awadalla, M.; Hassan, M.Z.; Zafar, A.; Drobni, Z.D.; Mahmood, S.S.; Zhang, L.; Coelho-Filho, O.R.; Suero-Abreu, G.A.; et al. Global Circumferential and Radial Strain Among Patients With Immune Checkpoint Inhibitor Myocarditis. JACC Cardiovasc. Imaging 2022, 15, 1883–1896. [Google Scholar] [CrossRef] [PubMed]
  15. Vasbinder, A.; Chen, Y.; Procureur, A.; Gradone, A.; Azam, T.U.; Perry, D.; Shadid, H.; Anderson, E.; Catalan, T.; Blakely, P.; et al. Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor–Induced Myocarditis. JACC CardioOncol. 2022, 4, 689–700. [Google Scholar] [CrossRef] [PubMed]
  16. Oishi, H.; Morimoto, R.; Shimoyama, Y.; Kuroda, K.; Urata, T.; Kondo, T.; Okumura, T.; Bando, Y.K.; Akiyama, M.; Murohara, T. Myocardial Vasculitis Associated With the Immune Checkpoint Inhibitor Pembrolizumab. JACC Case Rep. 2020, 2, 1937–1941. [Google Scholar] [CrossRef]
  17. Shalit, A.; Sarantis, P.; Koustas, E.; Trifylli, E.M.; Matthaios, D.; Karamouzis, M.V. Predictive Biomarkers for Immune-Related Endocrinopathies following Immune Checkpoint Inhibitors Treatment. Cancers 2023, 15, 375. [Google Scholar] [CrossRef]
  18. Iwamuro, M.; Tanaka, T.; Kono, Y.; Kawano, S.; Okada, H. Multiple White Plaques in the Esophagus: A Possible Case of Esophageal Mucosal Alteration Associated With Immune-Related Adverse Events of Immune Checkpoint Inhibitors. Cureus 2022, 14, e32710. [Google Scholar] [CrossRef]
  19. Reid, P.; Cappelli, L.C. Treatment of Rheumatic Adverse Events of Cancer Immunotherapy. Best Pract. Res. Clin. Rheumatol. 2022; ahead of print. [Google Scholar] [CrossRef]
  20. Quagliariello, V.; Passariello, M.; Di Mauro, A.; Cipullo, C.; Paccone, A.; Barbieri, A.; Palma, G.; Luciano, A.; Buccolo, S.; Bisceglia, I.; et al. Immune checkpoint inhibitor therapy increases systemic SDF-1, cardiac DAMPs Fibronectin-EDA, S100/Calgranulin, galectine-3, and NLRP3-MyD88-chemokine pathways. Front. Cardiovasc. Med. 2022, 9, 930797. [Google Scholar] [CrossRef]
  21. Quagliariello, V.; Passariello, M.; Rea, D.; Barbieri, A.; Iovine, M.; Bonelli, A.; Caronna, A.; Botti, G.; De Lorenzo, C.; Maurea, N. Evidences of CTLA-4 and PD-1 Blocking Agents-Induced Cardiotoxicity in Cellular and Preclinical Models. J. Pers. Med. 2020, 10, 179. [Google Scholar] [CrossRef]
  22. Suero-Abreu, G.A.; Zanni, M.V.; Neilan, T.G. Atherosclerosis with Immune Checkpoint Inhibitor Therapy: Evidence, Diagnosis, and Management: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022, 4, 598–615. [Google Scholar] [CrossRef]
  23. Thuny, F.; Naidoo, J.; Neilan, T.G. Cardiovascular complications of immune checkpoint inhibitors for cancer. Eur Heart J. 2022, 43, 4458–4468. [Google Scholar] [CrossRef]
  24. Poels, K.; van Leent, M.M.; Boutros, C.; Tissot, H.; Roy, S.; Meerwaldt, A.E.; Toner, Y.C.; Reiche, M.E.; Kusters, P.J.; Malinova, T.; et al. Immune Checkpoint Inhibitor Therapy Aggravates T Cell–Driven Plaque Inflammation in Atherosclerosis. JACC CardioOncol. 2020, 2, 599–610. [Google Scholar] [CrossRef] [PubMed]
  25. Carbone, F.; Ministrini, S.; Bonaventura, A.; Vecchié, A.; Minetti, S.; Bardi, N.; Elia, E.; Ansaldo, A.M.; Ferrara, D.; Rijavec, E.; et al. Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC. Eur. J. Clin. Investig. 2022, 52, e13668. [Google Scholar] [CrossRef]
  26. Tajiri, K.; Sekine, I. Atherosclerotic cardiovascular events associated with immune checkpoint inhibitors in cancer patients. Jpn. J. Clin. Oncol. 2022, 52, 659–664, Erratum in Jpn. J. Clin. Oncol. 2022, 52, 1358. [Google Scholar] [CrossRef]
  27. Sotler, T.; Šebeštjen, M. PCSK9 as an Atherothrombotic Risk Factor. Int. J. Mol. Sci. 2023, 24, 1966. [Google Scholar] [CrossRef]
  28. Luquero, A.; Vilahur, G.; Casani, L.; Badimon, L.; Borrell-Pages, M. Differential cholesterol uptake in liver cells: A role for PCSK9. FASEB J. 2022, 36, e22291. [Google Scholar] [CrossRef] [PubMed]
  29. Kuzmich, N.; Andresyuk, E.; Porozov, Y.; Tarasov, V.; Samsonov, M.; Preferanskaya, N.; Veselov, V.; Alyautdin, R. PCSK9 as a Target for Development of a New Generation of Hypolipidemic Drugs. Molecules 2022, 27, 434. [Google Scholar] [CrossRef]
  30. Wilkins, J.T.; Lloyd-Jones, D.M. Novel Lipid-Lowering Therapies to Reduce Cardiovascular Risk. JAMA 2021, 326, 266–267, Erratum in JAMA 2021, 326, 1637. [Google Scholar] [CrossRef]
  31. Rohrbach, S.; Li, L.; Novoyatleva, T.; Niemann, B.; Knapp, F.; Molenda, N.; Schulz, R. Impact of PCSK9 on CTRP9-Induced Metabolic Effects in Adult Rat Cardiomyocytes. Front. Physiol. 2021, 12, 593862. [Google Scholar] [CrossRef]
  32. Schmid, J.A. PCSK9 inhibition might increase endothelial inflammation. Atherosclerosis 2022, 362, 26–28. [Google Scholar] [CrossRef] [PubMed]
  33. Alannan, M.; Fatrouni, H.; Trézéguet, V.; Dittrich-Domergue, F.; Moreau, P.; Siegfried, G.; Liet, B.; Khatib, A.-M.; Grosset, C.F.; Badran, B.; et al. Targeting PCSK9 in Liver Cancer Cells Triggers Metabolic Exhaustion and Cell Death by Ferroptosis. Cells 2022, 12, 62. [Google Scholar] [CrossRef] [PubMed]
  34. Lee, J.H.; Hyung, S.; Lee, J.; Choi, S.-H. Visceral adiposity and systemic inflammation in the obesity paradox in patients with unresectable or metastatic melanoma undergoing immune checkpoint inhibitor therapy: A retrospective cohort study. J. Immunother. Cancer 2022, 10, e005226. [Google Scholar] [CrossRef]
  35. E Sise, M.; Wang, Q.; Seethapathy, H.; Moreno, D.; Harden, D.; Smith, R.N.; A Rosales, I.; Colvin, R.B.; Chute, S.; Cornell, L.D.; et al. Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis. J. Immunother. Cancer 2023, 11, e006222. [Google Scholar] [CrossRef] [PubMed]
  36. Yi, M.; Li, T.; Niu, M.; Wu, Y.; Zhao, Z.; Wu, K. TGF-β: A novel predictor and target for anti-PD-1/PD-L1 therapy. Front. Immunol. 2022, 13, 1061394. [Google Scholar] [CrossRef]
  37. Lin, Y.; Yuan, X.; Chen, L. Immune myocarditis related to sintilimab treatment in a patient with advanced lung adenocarcinoma: A case report. Front. Cardiovasc. Med. 2022, 9, 955527. [Google Scholar] [CrossRef]
  38. Kurozumi, A.; Sakamoto, K.; Nakagawa, T.; Matsunaga, F.; Shimomura, A.; Shimizu, C.; Hara, H.; Hiroi, Y. Atherosclerotic Progression Is Related to Immune-Related Adverse Events. Int. Heart J. 2022, 63, 293–298. [Google Scholar] [CrossRef] [PubMed]
  39. Agmon, I.N.; Ben Zadok, O.I.; Kornowski, R. The Potential Cardiotoxicity of Immune Checkpoint Inhibitors. J. Clin. Med. 2022, 11, 865. [Google Scholar] [CrossRef] [PubMed]
  40. Inno, A.; Chiampan, A.; Lanzoni, L.; Verzè, M.; Molon, G.; Gori, S. Immune Checkpoint Inhibitors and Atherosclerotic Vascular Events in Cancer Patients. Front. Cardiovasc. Med. 2021, 8, 652186. [Google Scholar] [CrossRef] [PubMed]
  41. Li, Y.; Yang, M.; Chen, X.; Zhang, R.; Li, J.; Zhang, X.; Zuo, P.; Ma, G. Effects of PCSK9 Inhibition on Coronary Atherosclerosis Regression of Nontarget Lesions after Primary Percutaneous Coronary Intervention in Acute Coronary Syndrome Patients. J. Interv. Cardiol. 2022, 2022, 4797529. [Google Scholar] [CrossRef]
  42. Luo, J.; Liao, W.; Wang, X.; Xu, R.; Li, W.; Li, W.; Liu, K.; Huang, K.; Ma, Y.; Wang, T.; et al. PCSK9 inhibitors for anti-inflammation in atherosclerosis: Protocol for a systematic review and meta-analysis of randomised controlled trials. BMJ Open 2022, 12, e062046. [Google Scholar] [CrossRef]
  43. Noto, D.; Arca, M.; Tarugi, P.; Cefalù, A.B.; Barbagallo, C.M.; Averna, M.R. Association between familial hypobetalipoproteinemia and the risk of diabetes. Is this the other side of the cholesterol–diabetes connection? A systematic review of literature. Acta Diabetol. 2017, 54, 111–122. [Google Scholar] [CrossRef] [PubMed]
  44. Huang, L.; Li, Y.; Cheng, Z.; Lv, Z.; Luo, S.; Xia, Y. PCSK9 Promotes Endothelial Dysfunction during Sepsis via the TLR4/MyD88/NF-κB and NLRP3 Pathways. Inflammation, 2022; ahead of print. [Google Scholar] [CrossRef]
  45. Xu, Q.; Zhao, Y.-M.; He, N.-Q.; Gao, R.; Xu, W.-X.; Zhuo, X.-J.; Ren, Z.; Wu, C.-Y.; Liu, L.-S. PCSK9: A emerging participant in heart failure. Biomed. Pharmacother. 2023, 158, 114106. [Google Scholar] [CrossRef] [PubMed]
  46. Aguilar-Ballester, M.; Hurtado-Genovés, G.; Taberner-Cortés, A.; Herrero-Cervera, A.; Martínez-Hervás, S.; González-Navarro, H. Therapies for the Treatment of Cardiovascular Disease Associated with Type 2 Diabetes and Dyslipidemia. Int. J. Mol. Sci. 2021, 22, 660. [Google Scholar] [CrossRef] [PubMed]
  47. Vlachopoulos, C.; Koutagiar, I.; Terentes-Printzios, D.; Skoumas, I.; Rigatou, A.; Miliou, A.; Skliros, A.-N.; Pantou, S.; Filis, K.; Tousoulis, D. Relationship of PCSK9 levels with indices of vascular function and subclinical atherosclerosis in patients with familial dyslipidemias. Hell. J. Cardiol. 2018, 60, 124–128. [Google Scholar] [CrossRef] [PubMed]
  48. Cacciottolo, P.J.; Kostapanos, M.S.; Sancho, E.H.; Pavey, H.; Kaloyirou, F.; Vamvaka, E.; Helmy, J.; Hubsch, A.; McEniery, C.M.; Wilkinson, I.B.; et al. Investigating the Lowest Threshold of Vascular Benefits from LDL Cholesterol Lowering with a PCSK9 mAb Inhibitor (Alirocumab) in Patients with Stable Cardiovascular Disease (INTENSITY-HIGH): Protocol and study rationale for a randomised, open label, parallel group, mechanistic study. BMJ Open 2021, 11, e037457. [Google Scholar] [CrossRef]
  49. Sawaguchi, J.; Saeki, Y.; Oda, M.; Takamura, T.-A.; Fujibayashi, K.; Wakasa, M.; Akao, H.; Kitayama, M.; Kawai, Y.; Kajinami, K. The circulating furin-cleaved/mature PCSK9 ratio has a potential prognostic significance in statin-naïve patients with acute ST elevation myocardial infarction. Atheroscler. Plus 2022, 50, 50–56. [Google Scholar] [CrossRef]
  50. Wang, S.; Fu, D.; Liu, H.; Peng, D. Independent association of PCSK9 with platelet reactivity in subjects without statin or antiplatelet agents. Front. Cardiovasc. Med. 2022, 9, 934914. [Google Scholar] [CrossRef]
  51. Papotti, B.; Adorni, M.P.; Marchi, C.; Zimetti, F.; Ronda, N.; Panighel, G.; Lupo, M.G.; Vilella, A.; Giuliani, D.; Ferri, N.; et al. PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease. Int. J. Mol. Sci. 2022, 23, 12192. [Google Scholar] [CrossRef]
  52. Gratton, J.; Finan, C.; Hingorani, A.D.; Humphries, S.E.; Futema, M. LDL-C Concentrations and the 12-SNP LDL-C Score for Polygenic Hypercholesterolaemia in Self-Reported South Asian, Black and Caribbean Participants of the UK Biobank. Front. Genet. 2022, 13, 845498. [Google Scholar] [CrossRef]
  53. Ostadal, P.; Steg, P.G.; Poulouin, Y.; Bhatt, D.L.; A Bittner, V.; Chua, T.; Diaz, R.; Goodman, S.G.; Huo, Y.; Jukema, J.W.; et al. Metabolic risk factors and effect of alirocumab on cardiovascular events after acute coronary syndrome: A post-hoc analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 2022, 10, 330–340. [Google Scholar] [CrossRef]
  54. Sabatine, M.S.; Leiter, L.A.; Wiviott, S.D.; Giugliano, R.; Deedwania, P.; De Ferrari, G.M.; Murphy, S.A.; Kuder, J.F.; Gouni-Berthold, I.; Lewis, B.S.; et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: A prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017, 5, 941–950. [Google Scholar] [CrossRef]
  55. Merleev, A.; Ji-Xu, A.; Toussi, A.; Tsoi, L.C.; Le, S.T.; Luxardi, G.; Xing, X.; Wasikowski, R.; Liakos, W.; Brüggen, M.-C.; et al. Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G. J. Clin. Investig. 2022, 7, 141193. [Google Scholar] [CrossRef]
  56. Seidah, N.G. The PCSK9 discovery, an inactive protease with varied functions in hypercholesterolemia, viral infections, and cancer. J. Lipid Res. 2021, 62, 100130. [Google Scholar] [CrossRef] [PubMed]
  57. Krempf, M.; Hopkins, P.N.; Bruckert, E.; Lee, S.; Donahue, S. Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations. Am. J. Cardiol. 2019, 125, 880–886. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Guo, Y.; Yan, B.; Tai, S.; Zhou, S.; Zheng, X.-L. PCSK9: Associated with cardiac diseases and their risk factors? Arch. Biochem. Biophys. 2020, 704, 108717. [Google Scholar] [CrossRef] [PubMed]
  59. Palee, S.; McSweeney, C.M.; Maneechote, C.; Moisescu, D.M.; Jaiwongkam, T.; Kerdphoo, S.; Chattipakorn, S.C.; Chattipakorn, N. PCSK9 inhibitor improves cardiac function and reduces infarct size in rats with ischaemia/reperfusion injury: Benefits beyond lipid-lowering effects. J. Cell. Mol. Med. 2019, 23, 7310–7319. [Google Scholar] [CrossRef] [Green Version]
  60. Li, X.; Dai, F.; Wang, H.; Wei, G.; Jiang, Q.; Yin, P.; Wang, S.; Ge, J.; Yang, C.; Wu, J.; et al. PCSK9 participates in oxidized-low density lipoprotein-induced myocardial injury through mitochondrial oxidative stress and Drp1-mediated mitochondrial fission. Clin. Transl. Med. 2022, 12, e729. [Google Scholar] [CrossRef]
  61. Ding, Z.; Wang, X.; Liu, S.; Shahanawaz, J.; Theus, S.; Fan, Y.; Deng, X.; Zhou, S.; Mehta, J. PCSK9 expression in the ischaemic heart and its relationship to infarct size, cardiac function, and development of autophagy. Cardiovasc. Res. 2018, 114, 1738–1751. [Google Scholar] [CrossRef] [PubMed]
  62. Wang, X.; Li, X.; Liu, S.; Brickell, A.N.; Zhang, J.; Wu, Z.; Zhou, S.; Ding, Z. PCSK9 regulates pyroptosis via mtDNA damage in chronic myocardial ischemia. Basic Res. Cardiol. 2020, 115, 66. [Google Scholar] [CrossRef]
  63. Huang, G.; Lu, X.; Duan, Z.; Zhang, K.; Xu, L.; Bao, H.; Xiong, X.; Lin, M.; Li, C.; Li, Y.; et al. PCSK9 Knockdown Can Improve Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy. Cardiovasc. Toxicol. 2022, 22, 951–961. [Google Scholar] [CrossRef] [PubMed]
  64. Cantin, C.; Garchitorena, M.J.; Escalona, R.; Carvajal, J.A.; Illanes, S.E.; Gutierrez, J.; Leiva, A. Increased Circulating Levels of PCSK9 and Pro-Atherogenic Lipoprotein Profile in Pregnant Women with Maternal Supraphysiological Hypercholesterolemia. Antioxidants 2022, 11, 869. [Google Scholar] [CrossRef] [PubMed]
  65. Quagliariello, V.; Vecchione, R.; De Capua, A.; Lagreca, E.; Iaffaioli, R.V.; Botti, G.; A Netti, P.; Maurea, N. Nano-Encapsulation of Coenzyme Q10 in Secondary and Tertiary Nano-Emulsions for Enhanced Cardioprotection and Hepatoprotection in Human Cardiomyocytes and Hepatocytes During Exposure to Anthracyclines and Trastuzumab. Int. J. Nanomed. 2020, 15, 4859–4876. [Google Scholar] [CrossRef] [PubMed]
  66. Quagliariello, V.; Coppola, C.; Mita, D.; Piscopo, G.; Iaffaioli, R.; Botti, G.; Maurea, N. Low doses of Bisphenol A have pro-inflammatory and pro-oxidant effects, stimulate lipid peroxidation and increase the cardiotoxicity of Doxorubicin in cardiomyoblasts. Environ. Toxicol. Pharmacol. 2019, 69, 1–8. [Google Scholar] [CrossRef]
  67. Byun, J.H.; Lebeau, P.F.; Platko, K.; Carlisle, R.E.; Faiyaz, M.; Chen, J.; MacDonald, M.E.; Makda, Y.; Yousof, T.; Lynn, E.G.; et al. Inhibitory Antibodies against PCSK9 Reduce Surface CD36 and Mitigate Diet-Induced Renal Lipotoxicity. Kidney360 2022, 3, 1394–1410. [Google Scholar] [CrossRef]
  68. Lüscher, T.F. Cholesterol production, accumulation, reverse transport, and excretion: Opportunities for statins, PPAR-α agonists, and PCSK9 inhibitors. Eur. Heart J. 2015, 36, 2965–2967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2022, 79, 1757–1780. [Google Scholar] [CrossRef]
  70. Nanna, M.G.; Nelson, A.J.; Haynes, K.; Shambhu, S.; Eapen, Z.; Cziraky, M.J.; Calvert, S.B.; Pagidipati, N.J.; Granger, C.B. Lipid-Lowering Treatment among Older Patients with Atherosclerotic Cardiovascular Disease. J. Am. Geriatr. Soc. 2022; ahead of print. [Google Scholar] [CrossRef]
  71. Likozar, A.R.; Šebeštjen, M. Smoking and diabetes attenuate beneficial effects of PSCK9 inhibitors on arterial wall properties in patients with very high lipoprotein (a) levels. Atheroscler. Plus 2022, 50, 1–9. [Google Scholar] [CrossRef]
  72. Ahamad, S.; Bhat, S.A. Recent Update on the Development of PCSK9 Inhibitors for Hypercholesterolemia Treatment. J. Med. Chem. 2022, 65, 15513–15539. [Google Scholar] [CrossRef]
  73. Goonewardena, S.N.; Rosenson, R.S. PCSK9: The Nexus of Lipoprotein Metabolism and Inflammation in COVID-19. J. Am. Coll. Cardiol. 2023, 81, 235–236. [Google Scholar] [CrossRef]
  74. Paré, G.; Chong, M.; Mohammadi-Shemirani, P. Lipoprotein(a) Cholesterol Masquerading as Low-Density Lipoprotein Cholesterol. J. Am. Coll. Cardiol. 2022, 79, 1047–1049. [Google Scholar] [CrossRef]
  75. Dai, N.; Chen, Z.; Zhou, F.; Zhou, Y.; Hu, N.; Duan, S.; Wang, W.; Yu, Y.; Zhang, L.; Qian, J.; et al. Association of Lipoprotein (a) With Coronary-Computed Tomography Angiography-Assessed High-Risk Coronary Disease Attributes and Cardiovascular Outcomes. Circ. Cardiovasc. Imaging 2022, 15, e014611. [Google Scholar] [CrossRef] [PubMed]
  76. Kaiser, Y.; Daghem, M.; Tzolos, E.; Meah, M.N.; Doris, M.K.; Moss, A.J.; Kwiecinski, J.; Kroon, J.; Nurmohamed, N.S.; van der Harst, P.; et al. Association of Lipoprotein(a) With Atherosclerotic Plaque Progression. J. Am. Coll. Cardiol. 2022, 79, 223–233. [Google Scholar] [CrossRef]
  77. Sheikhy, M.; Schrieber, S.J.; Sun, Q.; Gershuny, V.; Matta, M.K.; Bai, J.P.; Du, X.; Vegesna, G.; Shah, A.; Prentice, K.; et al. Considerations for Use of Pharmacodynamic Biomarkers to Support Biosimilar Development—(I) A Randomized Trial with PCSK9 Inhibitors. Clin. Pharmacol. Ther. 2022, 113, 71–79. [Google Scholar] [CrossRef] [PubMed]
  78. Parham, J.S.; Goldberg, A.C. Review of recent clinical trials and their impact on the treatment of hypercholesterolemia. Prog. Cardiovasc. Dis. 2022, 75, 90–96. [Google Scholar] [CrossRef]
  79. Chen, J.; Zhao, F.; Lei, C.; Qi, T.; Xue, X.; Meng, Y.; Zhang, W.; Zhang, H.; Wang, J.; Zhu, H.; et al. Effect of evolocumab on the progression of intraplaque neovascularization of the carotid based on contrast-enhanced ultrasonography (EPIC study): A prospective single-arm, open-label study. Front. Pharmacol. 2023, 13, 999224. [Google Scholar] [CrossRef]
  80. Erviti, J.; Wright, J.; Bassett, K.; Ben-Eltriki, M.; Jauca, C.; Saiz, L.C.; Leache, L.; Gutiérrez-Valencia, M.; Perry, T.L. Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: A reanalysis based on regulatory data. BMJ Open 2022, 12, e060172. [Google Scholar] [CrossRef] [PubMed]
  81. O’Donoghue, M.L.; Giugliano, R.P.; Wiviott, S.D.; Atar, D.; Keech, A.C.; Kuder, J.F.; Im, K.; Murphy, S.A.; Flores-Arredondo, J.H.; López, J.A.G.; et al. Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease. Circulation 2022, 146, 1109–1119. [Google Scholar] [CrossRef]
  82. Nicholls, S.J.; Nissen, S.E.; Prati, F.; Windecker, S.; Kataoka, Y.; Puri, R.; Hucko, T.; Kassahun, H.; Liao, J.; Somaratne, R.; et al. Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: Rationale and design of the randomized, placebo-controlled HUYGENS study. Cardiovasc. Diagn. Ther. 2021, 11, 120–129. [Google Scholar] [CrossRef]
  83. Luthra, G.; Shahbaz, M.; Almatooq, H.; Foucambert, P.; Esbrand, F.; Zafar, S.; Panthangi, V.; Kurupp, A.R.C.; Raju, A.; Khan, S. Exploring the Efficacy of Alirocumab and Evolocumab in Reducing Low-Density Lipoprotein (LDL) Cholesterol Levels in Patients With Familial Hypercholesterolemia: A Systematic Review. Cureus 2022, 14, e28930. [Google Scholar] [CrossRef]
  84. Nolain, P.; Djebli, N.; Brunet, A.; Fabre, D.; Khier, S. Combined Semi-mechanistic Target-Mediated Drug Disposition and Pharmacokinetic–Pharmacodynamic Models of Alirocumab, PCSK9, and Low-Density Lipoprotein Cholesterol in a Pooled Analysis of Randomized Phase I/II/III Studies. Eur. J. Drug Metab. Pharmacokinet. 2022, 47, 789–802. [Google Scholar] [CrossRef]
  85. Mahmood, T.; Minnier, J.; Ito, M.K.; Li, Q.H.; Koren, A.; Kam, I.W.; Fazio, S.; Shapiro, M.D. Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies. Eur. J. Prev. Cardiol. 2020, 28, 816–822. [Google Scholar] [CrossRef] [Green Version]
  86. Räber, L.; Ueki, Y.; Otsuka, T.; Losdat, S.; Häner, J.D.; Lonborg, J.; Fahrni, G.; Iglesias, J.F.; van Geuns, R.J.; Ondracek, A.S.; et al. Effect of Alirocumab Added to High-Intensity Statin Therapy on Coronary Atherosclerosis in Patients With Acute Myocardial Infarction: The PACMAN-AMI Randomized Clinical Trial. JAMA 2022, 327, 1771–1781. [Google Scholar] [CrossRef] [PubMed]
  87. Wang, E.Q.; Bukowski, J.F.; Yunis, C.; Shear, C.L.; Ridker, P.M.; Schwartz, P.F.; Baltrukonis, D. Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies. Biodrugs 2019, 33, 571–579. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Ridker, P.M.; Rose, L.M.; Kastelein, J.J.; Santos, R.D.; Wei, C.; Revkin, J.; Yunis, C.; Tardif, J.-C.; Shear, C.L. Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab. J. Clin. Lipidol. 2018, 12, 958–965. [Google Scholar] [CrossRef] [PubMed]
  89. Ridker, P.M.; Amarenco, P.; Brunell, R.; Glynn, R.J.; Jukema, J.W.; Kastelein, J.J.; Koenig, W.; Nissen, S.; Revkin, J.; Santos, R.D.; et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials. Am. Heart J. 2016, 178, 135–144. [Google Scholar] [CrossRef] [Green Version]
  90. Fazio, S.; Robertson, D.G.; Joh, T.; Wan, H.; Riel, T.; Forgues, P.; Baum, C.M.; Garzone, P.D.; Gumbiner, B. Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin. Cardiovasc. Ther. 2018, 36, e12308. [Google Scholar] [CrossRef] [Green Version]
  91. Wright, R.S.; Ray, K.K.; Raal, F.J.; Kallend, D.G.; Jaros, M.; Koenig, W.; Leiter, L.A.; Landmesser, U.; Schwartz, G.G.; Friedman, A.; et al. Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis. J. Am. Coll. Cardiol. 2021, 77, 1182–1193. [Google Scholar] [CrossRef]
  92. Scheen, A.J.; Wallemacq, C.; Lancellotti, P. Le médicament du mois. L’inclisiran (Leqvio®), hypocholestérolémiant puissant inhibant la synthèse de PCSK9 par la technique innovante de l’ARN interférent [Inclisiran (Leqvio®), a potent cholesterol-lowering agent by inhibiting PCSK9 using small interfering RNA-based innovative therapy]. Rev. Med. Liege. 2022, 77, 745–751. (In French) [Google Scholar]
  93. Ray, K.K.; Stoekenbroek, R.M.; Kallend, D.; Nishikido, T.; Leiter, L.A.; Landmesser, U.; Wright, R.S.; Wijngaard, P.L.J.; Kastelein, J.J.P. Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial. JAMA Cardiol. 2019, 4, 1067–1075. [Google Scholar] [CrossRef]
  94. Raal, F.; Ableson, M.; Blignaut, S.; Burgess, L.; Coetzer, S.; Ebrahim, I.; Gibbon, A.; van Rensburg, D.J.; Jaros, M.; Lombard, L.; et al. Safety and efficacy of inclisiran in South African patients at high cardiovascular risk: A subanalysis of the ORION phase III clinical trials. S. Afr. Med. J. 2022, 112, 426–432. [Google Scholar] [CrossRef]
  95. Koenig, W.; Conde, L.G.; Landmesser, U.; Leiter, L.A.; Ray, K.K.; Schwartz, G.G.; Wright, R.S.; Han, J.; Raal, F.J. Efficacy and Safety of Inclisiran in Patients with Polyvascular Disease: Pooled, Post Hoc Analysis of the ORION-9, ORION-10, and ORION-11 Phase 3 Randomized Controlled Trials. Cardiovasc. Drugs Ther. 2022; ahead of print. [Google Scholar] [CrossRef]
  96. Ray, K.K.; Kallend, D.; Leiter, L.A.; Raal, F.J.; Koenig, W.; Jaros, M.J.; Schwartz, G.G.; Landmesser, U.; Garcia Conde, L.; Wright, R.S.; et al. Effect of inclisiran on lipids in primary prevention: The ORION-11 trial. Eur. Heart J. 2022, 43, 5047–5057. [Google Scholar] [CrossRef]
  97. Warden, B.A.; Duell, P.B. Inclisiran: A Novel Agent for Lowering Apolipoprotein B–containing Lipoproteins. J. Cardiovasc. Pharmacol. 2021, 78, e157–e174. [Google Scholar] [CrossRef]
  98. Available online: https://clinicaltrials.gov/ct2/show/NCT03705234 (accessed on 25 January 2023).
  99. Mehranzadeh, E.; Crende, O.; Badiola, I.; Garcia-Gallastegi, P. What Are the Roles of Proprotein Convertases in the Immune Escape of Tumors? Biomedicines 2022, 10, 3292. [Google Scholar] [CrossRef]
  100. Seidah, N.G.; Prat, A. The Multifaceted Biology of PCSK9. Endocr. Rev. 2021, 43, 558–582. [Google Scholar] [CrossRef]
  101. Seidah, N.G.; Garçon, D. Expanding Biology of PCSK9: Roles in Atherosclerosis and Beyond. Curr. Atheroscler. Rep. 2022, 24, 821–830. [Google Scholar] [CrossRef]
  102. Fu, T.; Guan, Y.; Xu, J.; Wang, Y. APP, APLP2 and LRP1 interact with PCSK9 but are not required for PCSK9-mediated degradation of the LDLR in vivo. Biochim. et Biophys. Acta BBA-Mol. Cell Biol. Lipids 2017, 1862, 883–889. [Google Scholar] [CrossRef]
  103. Liu, C.; Chen, J.; Chen, H.; Zhang, T.; He, D.; Luo, Q.; Chi, J.; Hong, Z.; Liao, Y.; Zhang, S.; et al. PCSK9 Inhibition: From Current Advances to Evolving Future. Cells 2022, 11, 2972. [Google Scholar] [CrossRef]
  104. Carey, S.T.; Bridgeman, C.; Jewell, C.M. Biomaterial Strategies for Selective Immune Tolerance: Advances and Gaps. Adv. Sci. 2023, 2, e2205105. [Google Scholar] [CrossRef] [PubMed]
  105. Li, M.; Yang, Y.; Wei, J.; Cun, X.; Lu, Z.; Qiu, Y.; Zhang, Z.; He, Q. Enhanced chemo-immunotherapy against melanoma by inhibition of cholesterol esterification in CD8+ T cells. Nanomedicine 2018, 14, 2541–2550. [Google Scholar] [CrossRef] [PubMed]
  106. Yin, R.-X.; Wu, D.-F.; Miao, L.; Aung, L.H.H.; Cao, X.-L.; Yan, T.-T.; Long, X.-J.; Liu, W.-Y.; Zhang, L.; Li, M. Several genetic polymorphisms interact with overweight/obesity to influence serum lipid levels. Cardiovasc. Diabetol. 2012, 11, 123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Liang, D.M.; Li, C.M.; Tu, Y.M.; Li, Z.M.; Zhang, M. Additive effects of ezetimibe, evolocumab, and alirocumab on plaque burden and lipid content as assessed by intravascular ultrasound: A PRISMA-compliant meta-analysis. Medicine 2022, 101, e31199. [Google Scholar] [CrossRef] [PubMed]
  108. Xie, L.; Meng, Z. Immunomodulatory Effect of Locoregional Therapy in the Tumor Microenvironment. Mol. Ther. 2023; ahead of print. [Google Scholar] [CrossRef]
  109. Goksøyr, L.; Skrzypczak, M.; Sampson, M.; Nielsen, M.A.; Salanti, A.; Theander, T.G.; Remaley, A.T.; De Jongh, W.A.; Sander, A.F. A cVLP-Based Vaccine Displaying Full-Length PCSK9 Elicits a Higher Reduction in Plasma PCSK9 Than Similar Peptide-Based cVLP Vaccines. Vaccines 2022, 11, 2. [Google Scholar] [CrossRef]
  110. Mbikay, M.; Chrétien, M. The biological relevance of PCSK9: When less is better…. Biochem. Cell Biol. 2022, 100, 189–198. [Google Scholar] [CrossRef]
  111. Zou, Y.; Chen, Z.; Zhang, X.; Yu, J.; Xu, H.; Cui, J.; Li, Y.; Niu, Y.; Zhou, C.; Xia, J.; et al. Targeting PCSK9 Ameliorates Graft Vascular Disease in Mice by Inhibiting NLRP3 Inflammasome Activation in Vascular Smooth Muscle Cells. Front. Immunol. 2022, 13, 894789. [Google Scholar] [CrossRef]
  112. Charbe, N.B.; Lagos, C.F.; Ortiz, C.A.V.; Tambuwala, M.; Palakurthi, S.S.; Zacconi, F.C. PCSK9 conjugated liposomes for targeted delivery of paclitaxel to the cancer cell: A proof-of-concept study. Biomed. Pharmacother. 2022, 153, 113428. [Google Scholar] [CrossRef]
  113. Piao, M.-X.; Bai, J.-W.; Zhang, P.-F.; Zhang, Y.-Z. PCSK9 regulates apoptosis in human neuroglioma u251 cells via mitochondrial signaling pathways. Int. J. Clin. Exp. Pathol. 2015, 8, 2787–2794. [Google Scholar] [PubMed]
  114. Douna, H.; Smit, V.; van Puijvelde, G.H.; Kiss, M.G.; Binder, C.J.; Bot, L.; Kuchroo, V.K.; Lichtman, A.H.; Kuiper, J.; Foks, A.C. Tim-1 mucin domain-mutant mice display exacerbated atherosclerosis. Atherosclerosis 2022, 352, 1–9. [Google Scholar] [CrossRef]
  115. Abdelwahed, K.S.; Siddique, A.B.; Qusa, M.H.; King, J.A.; Souid, S.; Elmageed, Z.Y.A.; El Sayed, K.A. PCSK9 Axis-Targeting Pseurotin A as a Novel Prostate Cancer Recurrence Suppressor Lead. ACS Pharmacol. Transl. Sci. 2021, 4, 1771–1781. [Google Scholar] [CrossRef]
  116. Saha, S.; Singh, A.; Kumar, P.; Sonkar, A.B.; Gautam, A.K.; Verma, A.; Maity, B.; Tiwari, H.; Sahoo, N.G.; Keshari, A.K.; et al. A Comprehensive Review on PCSK9 as Mechanistic Target Approach in Cancer Therapy. Mini-Rev. Med. Chem. 2021; ahead of print. [Google Scholar] [CrossRef]
  117. Xia, X.-D.; Peng, Z.-S.; Gu, H.-M.; Wang, M.; Wang, G.-Q.; Zhang, D.-W. Regulation of PCSK9 Expression and Function: Mechanisms and Therapeutic Implications. Front. Cardiovasc. Med. 2021, 8, 764038. [Google Scholar] [CrossRef] [PubMed]
  118. Lim, S.A.; Wei, J.; Nguyen, T.-L.M.; Shi, H.; Su, W.; Palacios, G.; Dhungana, Y.; Chapman, N.M.; Long, L.; Saravia, J.; et al. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 2021, 591, 306–311. [Google Scholar] [CrossRef]
  119. McBrearty, N.; Cho, C.; Chen, J.; Zahedi, F.; Peck, A.R.; Radaelli, E.; Assenmacher, C.A.; Pavlak, C.; Devine, A.; Yu, P.; et al. Tumor Suppressive and Immune-Stimulating Roles of Cholesterol 25-Hydroxylase in Pancreatic Cancer Cells. Mol. Cancer Res. 2022; OF1–OF12, ahead of print. [Google Scholar] [CrossRef]
  120. Yuan, J.; Cai, T.; Zheng, X.; Ren, Y.; Qi, J.; Lu, X.; Chen, H.; Lin, H.; Chen, Z.; Liu, M.; et al. Correction to: Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein Cell 2022, 13, 694–700, Erratum in Protein Cell 2021, 12, 240–260. [Google Scholar] [CrossRef]
  121. Mahboobnia, K.; Pirro, M.; Marini, E.; Grignani, F.; Bezsonov, E.E.; Jamialahmadi, T.; Sahebkar, A. PCSK9 and cancer: Rethinking the link. Biomed. Pharmacother. 2021, 140, 111758. [Google Scholar] [CrossRef] [PubMed]
  122. Abuelezz, S.A.; Hendawy, N. HMGB1/RAGE/TLR4 axis and glutamate as novel targets for PCSK9 inhibitor in high fat cholesterol diet induced cognitive impairment and amyloidosis. Life Sci. 2021, 273, 119310. [Google Scholar] [CrossRef]
  123. Nishikawa, R.; Furuhashi, M.; Hori, M.; Ogura, M.; Harada-Shiba, M.; Okada, T.; Koseki, M.; Kujiraoka, T.; Hattori, H.; Ito, R.; et al. A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the PCSK9 and ABCG5 Genes and Type I CD36 Deficiency. J. Atheroscler. Thromb. 2022, 29, 551–557. [Google Scholar] [CrossRef] [PubMed]
  124. Wang, L.; Li, S.; Luo, H.; Lu, Q.; Yu, S. PCSK9 promotes the progression and metastasis of colon cancer cells through regulation of EMT and PI3K/AKT signaling in tumor cells and phenotypic polarization of macrophages. J. Exp. Clin. Cancer Res. 2022, 41, 303. [Google Scholar] [CrossRef]
  125. Chong, E.W.; Joncas, F.-H.; Seidah, N.G.; Calon, F.; Diorio, C.; Gangloff, A. Circulating levels of PCSK9, ANGPTL3 and Lp(a) in stage III breast cancers. BMC Cancer 2022, 22, 1049. [Google Scholar] [CrossRef]
  126. Wang, R.; Liu, H.; He, P.; An, D.; Guo, X.; Zhang, X.; Feng, M. Inhibition of PCSK9 enhances the antitumor effect of PD-1 inhibitor in colorectal cancer by promoting the infiltration of CD8+ T cells and the exclusion of Treg cells. Front. Immunol. 2022, 13, 947756. [Google Scholar] [CrossRef]
  127. Sun, Y.; Zhang, H.; Meng, J.; Guo, F.; Ren, D.; Wu, H.; Jin, X. S-palmitoylation of PCSK9 induces sorafenib resistance in liver cancer by activating the PI3K/AKT pathway. Cell Rep. 2022, 40, 111194. [Google Scholar] [CrossRef]
  128. Wong, C.C.; Wu, J.-L.; Ji, F.; Kang, W.; Bian, X.; Chen, H.; Chan, L.-S.; Luk, S.T.Y.; Tong, S.; Xu, J.; et al. The cholesterol uptake regulator PCSK9 promotes and is a therapeutic target in APC/KRAS-mutant colorectal cancer. Nat. Commun. 2022, 13, 3971. [Google Scholar] [CrossRef]
  129. Shu, X.; Wu, J.; Zhang, T.; Ma, X.; Du, Z.; Xu, J.; You, J.; Wang, L.; Chen, N.; Luo, M.; et al. Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes PCSK9–Dependent Adipose Insulin Resistance. Nutrients 2022, 14, 5314. [Google Scholar] [CrossRef] [PubMed]
  130. Tchéoubi, S.E.R.; Akpovi, C.D.; Coppée, F.; Declèves, A.-E.; Laurent, S.; Agbangla, C.; Burtea, C. Molecular and cellular biology of PCSK9: Impact on glucose homeostasis. J. Drug Target. 2022, 30, 948–960. [Google Scholar] [CrossRef]
  131. Sun, X.; Essalmani, R.; Day, R.; Khatib, A.M.; Seidah, N.G.; Prat, A. Proprotein Convertase Subtilisin/Kexin Type 9 Deficiency Reduces Melanoma Metastasis in Liver. Neoplasia 2012, 14, 1122–1131. [Google Scholar] [CrossRef] [Green Version]
  132. Sun, L.; Ding, H.; Jia, Y.; Shi, M.; Guo, D.; Yang, P.; Wang, Y.; Liu, F.; Zhang, Y.; Zhu, Z. Associations of genetically proxied inhibition of HMG-CoA reductase, NPC1L1, and PCSK9 with breast cancer and prostate cancer. Breast Cancer Res. 2022, 24, 12. [Google Scholar] [CrossRef] [PubMed]
  133. Sanz, D.J.; Raivola, J.; Karvonen, H.; Arjama, M.; Barker, H.; Murumägi, A.; Ungureanu, D. Evaluating Targeted Therapies in Ovarian Cancer Metabolism: Novel Role for PCSK9 and Second Generation mTOR Inhibitors. Cancers 2021, 13, 3727. [Google Scholar] [CrossRef]
  134. Bonaventura, A.; Grossi, F.; Carbone, F.; Vecchié, A.; Minetti, S.; Bardi, N.; Elia, E.; Ansaldo, A.M.; Ferrara, D.; Rijavec, E.; et al. Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: A pilot study. Cancer Immunol. Immunother. 2019, 68, 1351–1358. [Google Scholar] [CrossRef] [PubMed]
  135. Guo, W.; Gao, H.; Li, H.; Ge, S.; Zhang, F.; Wang, L.; Shi, H.; Han, A. Self-Assembly of a Multifunction DNA Tetrahedron for Effective Delivery of Aptamer PL1 and Pcsk9 siRNA Potentiate Immune Checkpoint Therapy for Colorectal Cancer. ACS Appl. Mater. Interfaces 2022, 14, 31634–31644. [Google Scholar] [CrossRef]
  136. Liu, X.; Bao, X.; Hu, M.; Chang, H.; Jiao, M.; Cheng, J.; Xie, L.; Huang, Q.; Li, F.; Li, C.-Y. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature 2020, 588, 693–698. [Google Scholar] [CrossRef]
  137. Carbone, A.; Bottino, R.; Russo, V.M.; D’Andrea, A.M.; Liccardo, B.; Maurea, N.; Quagliariello, V.; Cimmino, G.M.; Golino, P.M. Takotsubo Cardiomyopathy as Epiphenomenon of Cardiotoxicity in Patients With Cancer: A Meta-summary of Case Reports. J. Cardiovasc. Pharmacol. 2021, 78, e20–e29. [Google Scholar] [CrossRef] [PubMed]
  138. Li, Y.; Liang, X.; Li, H.; Chen, X. Comparative efficacy and safety of immune checkpoint inhibitors for unresectable advanced melanoma: A systematic review and network meta-analysis. Int. Immunopharmacol. 2023, 115, 109657. [Google Scholar] [CrossRef]
  139. Available online: https://clinicaltrials.gov/ct2/show/NCT04586894 (accessed on 26 January 2023).
  140. Available online: https://clinicaltrials.gov/ct2/show/NCT03709771 (accessed on 26 January 2023).
  141. Available online: https://clinicaltrials.gov/ct2/show/NCT04115410 (accessed on 26 January 2023).
Cancers 15 01397 g001 550
Figure 1. Cancer patients treated with ICIs therapies (i.e., PD-1 or PDL-1 or CTLA-4 blocking agents or OX40 agonists) increases endothelial DAMPs, including Galectine-3, cytokines, chemokines, growth factors, and hs-CRP that are associated with plaque progression and instability.
Figure 1. Cancer patients treated with ICIs therapies (i.e., PD-1 or PDL-1 or CTLA-4 blocking agents or OX40 agonists) increases endothelial DAMPs, including Galectine-3, cytokines, chemokines, growth factors, and hs-CRP that are associated with plaque progression and instability.
Cancers 15 01397 g001
Cancers 15 01397 g002 550
Figure 2. PCSK9 chemical structure. The structure of PCSK9 reveals four major components in the pre-processed protein: the signal peptide (residues 1–30); the N-terminal pro-domain (residues 31–152); the catalytic domain (residues 153–425); and the C-terminal domain (residues 426–692), which is further divided into three modules.
Figure 2. PCSK9 chemical structure. The structure of PCSK9 reveals four major components in the pre-processed protein: the signal peptide (residues 1–30); the N-terminal pro-domain (residues 31–152); the catalytic domain (residues 153–425); and the C-terminal domain (residues 426–692), which is further divided into three modules.
Cancers 15 01397 g002
Cancers 15 01397 g003 550
Figure 3. PCSK9 role in cancer immune-recognition. PCSK9 induces lysosomal degradation of MHC-I after binding to a cancer antigen, thus reducing cancer membrane MHC-I density, making the tumor cell immune-irresponsive (peripheral immune tolerance). When PCSK9 is blocked by monoclonal antibodies, MHC-I is recycled after binding to a cancer antigen, therefore allowing the recognition of the MHC-I-Antigen complex by the TCR (signal 1) which, thanks to the type 2 signal (CD28-CD8 binding), allows the activation, proliferation, and survival of the T lymphocyte and the consequent rupture of the peripheral immune tolerance.
Figure 3. PCSK9 role in cancer immune-recognition. PCSK9 induces lysosomal degradation of MHC-I after binding to a cancer antigen, thus reducing cancer membrane MHC-I density, making the tumor cell immune-irresponsive (peripheral immune tolerance). When PCSK9 is blocked by monoclonal antibodies, MHC-I is recycled after binding to a cancer antigen, therefore allowing the recognition of the MHC-I-Antigen complex by the TCR (signal 1) which, thanks to the type 2 signal (CD28-CD8 binding), allows the activation, proliferation, and survival of the T lymphocyte and the consequent rupture of the peripheral immune tolerance.
Cancers 15 01397 g003
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Quagliariello, V.; Bisceglia, I.; Berretta, M.; Iovine, M.; Canale, M.L.; Maurea, C.; Giordano, V.; Paccone, A.; Inno, A.; Maurea, N. PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology. Cancers 2023, 15, 1397. https://doi.org/10.3390/cancers15051397

AMA Style

Quagliariello V, Bisceglia I, Berretta M, Iovine M, Canale ML, Maurea C, Giordano V, Paccone A, Inno A, Maurea N. PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology. Cancers. 2023; 15(5):1397. https://doi.org/10.3390/cancers15051397

Chicago/Turabian Style

Quagliariello, Vincenzo, Irma Bisceglia, Massimiliano Berretta, Martina Iovine, Maria Laura Canale, Carlo Maurea, Vienna Giordano, Andrea Paccone, Alessandro Inno, and Nicola Maurea. 2023. "PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology" Cancers 15, no. 5: 1397. https://doi.org/10.3390/cancers15051397

APA Style

Quagliariello, V., Bisceglia, I., Berretta, M., Iovine, M., Canale, M. L., Maurea, C., Giordano, V., Paccone, A., Inno, A., & Maurea, N. (2023). PCSK9 Inhibitors in Cancer Patients Treated with Immune-Checkpoint Inhibitors to Reduce Cardiovascular Events: New Frontiers in Cardioncology. Cancers, 15(5), 1397. https://doi.org/10.3390/cancers15051397

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop