Journal Article

Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer

Bao, Xuhui, Li, Chuan-Yuan, Huang, Qian, Li, Fang, Xie, Liyi, Hu, Mengjie, Liu, Xinjian, Chang, Hanman, Cheng, Jin, Jiao, Meng

2020

Overview

Despite its success in achieving the long-term survival of 10–30% of treated individuals, immune therapy is still ineffective for most patients with cancer 1 , 2 . Many efforts are therefore underway to identify new approaches that enhance such immune ‘checkpoint’ therapy 3 – 5 (so called because its aim is to block proteins that inhibit checkpoint signalling pathways in T cells, thereby freeing those immune cells to target cancer cells). Here we show that inhibiting PCSK9—a key protein in the regulation of cholesterol metabolism 6 – 8 —can boost the response of tumours to immune checkpoint therapy, through a mechanism that is independent of PCSK9’s cholesterol-regulating functions. Deleting the PCSK9 gene in mouse cancer cells substantially attenuates or prevents their growth in mice in a manner that depends on cytotoxic T cells. It also enhances the efficacy of immune therapy that is targeted at the checkpoint protein PD1. Furthermore, clinically approved PCSK9-neutralizing antibodies synergize with anti-PD1 therapy in suppressing tumour growth in mouse models of cancer. Inhibiting PCSK9—either through genetic deletion or using PCSK9 antibodies—increases the expression of major histocompatibility protein class I (MHC I) proteins on the tumour cell surface, promoting robust intratumoral infiltration of cytotoxic T cells. Mechanistically, we find that PCSK9 can disrupt the recycling of MHC I to the cell surface by associating with it physically and promoting its relocation and degradation in the lysosome. Together, these results suggest that inhibiting PCSK9 is a promising way to enhance immune checkpoint therapy for cancer. Inhibiting the PCSK9 protein, a regulator of cholesterol metabolism, enhances immune checkpoint therapy in mouse models of cancer, in a manner that depends on the regulation of antigen-presenting MHC I molecules.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/31 / 13/51 / 13/95 / 14/1 / 14/19 / 38 / 631/67/1059/2325 / 631/67/1059/2326 / 631/67/327 / 64 / 64/60 / 82 / 82/1 / 82/83 / Animal models / Animals / Antibodies / Antibodies, Neutralizing - immunology / Antibodies, Neutralizing - pharmacology / Antibodies, Neutralizing - therapeutic use / Cancer / Care and treatment / Cell Line, Tumor / Cell surface / Cholesterol / CRISPR / Cytotoxicity / Disease Models, Animal / Enzymes / Experiments / Female / Histocompatibility Antigens Class I - immunology / Histocompatibility Antigens Class I - metabolism / Humanities and Social Sciences / Humans / Immune checkpoint / Immune Checkpoint Inhibitors - pharmacology / Immune Checkpoint Inhibitors - therapeutic use / Immune system / Immunotherapy / Immunotherapy - methods / Low density lipoprotein receptors / Lymphocytes / Lymphocytes T / Lysosomes - metabolism / Major histocompatibility complex / Metabolism / Metastases / Methods / Mice / multidisciplinary / Neoplasms - drug therapy / Neoplasms - immunology / Neoplasms - metabolism / Neoplasms - pathology / PD-1 protein / Physiological aspects / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Proprotein Convertase 9 - antagonists & inhibitors / Proprotein Convertase 9 - deficiency / Proprotein Convertase 9 - genetics / Proprotein Convertase 9 - immunology / Proteins / Relocation / Science / Science (multidisciplinary) / Signal transduction / Survival / Synergism / T-Lymphocytes, Cytotoxic - cytology / T-Lymphocytes, Cytotoxic - immunology / Therapy / Tumors / Xenograft Model Antitumor Assays