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PCSK9 inhibition potentiates cancer immune checkpoint therapy

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 meta...

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Autores principales: Liu, Xinjian, Bao, Xuhui, Hu, Mengjie, Chang, Hanman, Jiao, Meng, Cheng, Jin, Xie, Liyi, Huang, Qian, Li, Fang, Li, Chuan-Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770056/
https://www.ncbi.nlm.nih.gov/pubmed/33177715
http://dx.doi.org/10.1038/s41586-020-2911-7
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author Liu, Xinjian
Bao, Xuhui
Hu, Mengjie
Chang, Hanman
Jiao, Meng
Cheng, Jin
Xie, Liyi
Huang, Qian
Li, Fang
Li, Chuan-Yuan
author_facet Liu, Xinjian
Bao, Xuhui
Hu, Mengjie
Chang, Hanman
Jiao, Meng
Cheng, Jin
Xie, Liyi
Huang, Qian
Li, Fang
Li, Chuan-Yuan
author_sort Liu, Xinjian
collection PubMed
description 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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spelling pubmed-77700562021-05-11 PCSK9 inhibition potentiates cancer immune checkpoint therapy Liu, Xinjian Bao, Xuhui Hu, Mengjie Chang, Hanman Jiao, Meng Cheng, Jin Xie, Liyi Huang, Qian Li, Fang Li, Chuan-Yuan Nature Article 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. 2020-11-11 2020-12 /pmc/articles/PMC7770056/ /pubmed/33177715 http://dx.doi.org/10.1038/s41586-020-2911-7 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Reprints and permissions information is available at www.nature.com/reprints (http://www.nature.com/reprints) .
spellingShingle Article
Liu, Xinjian
Bao, Xuhui
Hu, Mengjie
Chang, Hanman
Jiao, Meng
Cheng, Jin
Xie, Liyi
Huang, Qian
Li, Fang
Li, Chuan-Yuan
PCSK9 inhibition potentiates cancer immune checkpoint therapy
title PCSK9 inhibition potentiates cancer immune checkpoint therapy
title_full PCSK9 inhibition potentiates cancer immune checkpoint therapy
title_fullStr PCSK9 inhibition potentiates cancer immune checkpoint therapy
title_full_unstemmed PCSK9 inhibition potentiates cancer immune checkpoint therapy
title_short PCSK9 inhibition potentiates cancer immune checkpoint therapy
title_sort pcsk9 inhibition potentiates cancer immune checkpoint therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770056/
https://www.ncbi.nlm.nih.gov/pubmed/33177715
http://dx.doi.org/10.1038/s41586-020-2911-7
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