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

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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.

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2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: Executive Summary

Paul A Heidenreich, Biykem Bozkurt, David Aguilar … (2022)

The "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure" replaces the "2013 ACCF/AHA Guideline for the Management of Heart Failure" and the "2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure." The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure.

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PCSK9 inhibition potentiates cancer immune checkpoint therapy

Xinjian Liu, Xuhui Bao, Mengjie Hu … (2020)

Despite its great success, cancer immune therapy is still of limited efficacy in the majority of cancer patients 1 , 2 . Many efforts are underway to identify novel approaches to enhance immune checkpoint therapy 3 – 5 . Here we show that inhibition of PCSK9, a key protein in regulating cholesterol metabolism 6 – 8 , can boost tumor response to immune checkpoint therapy, albeit through a mechanism independent of its cholesterol regulating functions. Deletion of the PCSK9 gene in murine cancer cells significantly attenuated or prevented their growth in mice in a cytotoxic T-cell-dependent manner. It also enhanced the efficacy of anti-PD1 immune checkpoint therapy significantly. Furthermore, clinically approved PCSK9-neutralizing antibodies could synergize with anti-PD1 therapy in suppressing tumor growth in murine tumor models. PCSK9 inhibition, either through genetic deletion or PCSK9 antibodies, caused a significant increase in tumor cell surface major histocompatibility protein class I (MHC I) expression, which promoted robust intratumoral infiltration of cytotoxic T-cells. Mechanistically, we discovered that PCSK9 could disrupt the recycling of MHC I to the cell surface by promoting its relocation and degradation in the lysosome through physical association. Taken together, we believe PCSK9 inhibition is a promising strategy to enhance cancer immune checkpoint therapy.

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Lipid signalling enforces T _reg cell functional specialization in tumours

Seon Ah Lim, Jun Ji Wei, Thanh-Long Nguyen … (2021)

Regulatory T (T reg ) cells are essential for immune tolerance 1 but also drive immunosuppression in the tumour microenvironment (TME) 2 . Therapeutic targeting of T reg cells in cancer requires the identification of context-specific mechanisms for T reg cell function. Here we demonstrate that inhibition of sterol regulatory element-binding protein (SREBP)-dependent lipid synthesis and metabolic signalling in T reg cells unleashes effective antitumour immune responses without autoimmune toxicity. SREBP activity is upregulated in intratumoural T reg cells, and T reg cell-specific deletion of SCAP, an obligatory factor for SREBP activity, inhibits tumour growth and boosts anti-PD-1 immunotherapy, associated with uncontrolled IFN-γ production and impaired function of intratumoural T reg cells. Mechanistically, SCAP/SREBP signalling coordinates lipid synthetic programs and inhibitory receptor signalling in T reg cells. First, de novo fatty acid synthesis mediated by fatty acid synthase (FASN) contributes to functional maturation of T reg cells, and loss of FASN in T reg cells inhibits tumour growth. Second, T reg cells show enhanced Pdcd1 expression in tumours in a process dependent on SREBP activity that further signals to mevalonate metabolism-driven protein geranylgeranylation, and blocking PD-1 or SREBP signaling results in dysregulated PI3K activation in intratumoural T reg cells. Our findings establish that metabolic reprogramming enforces T reg cell functional specialization in tumours, pointing to new avenues to target T reg cells for cancer therapy.