Cargando…

Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma

OBJECTIVE: Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate...

Descripción completa

Detalles Bibliográficos
Autores principales: Xiong, Zhewen, Chan, Stephen Lam, Zhou, Jingying, Vong, Joaquim S.L., Kwong, Tsz Tung, Zeng, Xuezhen, Wu, Haoran, Cao, Jianquan, Tu, Yalin, Feng, Yu, Yang, Weiqin, Wong, Patrick Pak-Chun, Si-Tou, Willis Wai-Yiu, Liu, Xiaoyu, Wang, Jing, Tang, Wenshu, Liang, Zhixian, Lu, Jiahuan, Li, Ka Man, Low, Jie-Ting, Chan, Michael Wing-Yan, Leung, Howard H.W., Chan, Anthony W.H., To, Ka-Fai, Yip, Kevin Yuk-Lap, Lo, Yuk Ming Dennis, Sung, Joseph Jao-Yiu, Cheng, Alfred Sze-Lok
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10423534/
https://www.ncbi.nlm.nih.gov/pubmed/37019619
http://dx.doi.org/10.1136/gutjnl-2022-328364
_version_ 1785089474075557888
author Xiong, Zhewen
Chan, Stephen Lam
Zhou, Jingying
Vong, Joaquim S.L.
Kwong, Tsz Tung
Zeng, Xuezhen
Wu, Haoran
Cao, Jianquan
Tu, Yalin
Feng, Yu
Yang, Weiqin
Wong, Patrick Pak-Chun
Si-Tou, Willis Wai-Yiu
Liu, Xiaoyu
Wang, Jing
Tang, Wenshu
Liang, Zhixian
Lu, Jiahuan
Li, Ka Man
Low, Jie-Ting
Chan, Michael Wing-Yan
Leung, Howard H.W.
Chan, Anthony W.H.
To, Ka-Fai
Yip, Kevin Yuk-Lap
Lo, Yuk Ming Dennis
Sung, Joseph Jao-Yiu
Cheng, Alfred Sze-Lok
author_facet Xiong, Zhewen
Chan, Stephen Lam
Zhou, Jingying
Vong, Joaquim S.L.
Kwong, Tsz Tung
Zeng, Xuezhen
Wu, Haoran
Cao, Jianquan
Tu, Yalin
Feng, Yu
Yang, Weiqin
Wong, Patrick Pak-Chun
Si-Tou, Willis Wai-Yiu
Liu, Xiaoyu
Wang, Jing
Tang, Wenshu
Liang, Zhixian
Lu, Jiahuan
Li, Ka Man
Low, Jie-Ting
Chan, Michael Wing-Yan
Leung, Howard H.W.
Chan, Anthony W.H.
To, Ka-Fai
Yip, Kevin Yuk-Lap
Lo, Yuk Ming Dennis
Sung, Joseph Jao-Yiu
Cheng, Alfred Sze-Lok
author_sort Xiong, Zhewen
collection PubMed
description OBJECTIVE: Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting. DESIGN: Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481). RESULTS: Anti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8(+) T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8(+) T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types. CONCLUSION: We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC.
format Online
Article
Text
id pubmed-10423534
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BMJ Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-104235342023-08-14 Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma Xiong, Zhewen Chan, Stephen Lam Zhou, Jingying Vong, Joaquim S.L. Kwong, Tsz Tung Zeng, Xuezhen Wu, Haoran Cao, Jianquan Tu, Yalin Feng, Yu Yang, Weiqin Wong, Patrick Pak-Chun Si-Tou, Willis Wai-Yiu Liu, Xiaoyu Wang, Jing Tang, Wenshu Liang, Zhixian Lu, Jiahuan Li, Ka Man Low, Jie-Ting Chan, Michael Wing-Yan Leung, Howard H.W. Chan, Anthony W.H. To, Ka-Fai Yip, Kevin Yuk-Lap Lo, Yuk Ming Dennis Sung, Joseph Jao-Yiu Cheng, Alfred Sze-Lok Gut Hepatology OBJECTIVE: Therapy-induced tumour microenvironment (TME) remodelling poses a major hurdle for cancer cure. As the majority of patients with hepatocellular carcinoma (HCC) exhibits primary or acquired resistance to antiprogrammed cell death (ligand)-1 (anti-PD-[L]1) therapies, we aimed to investigate the mechanisms underlying tumour adaptation to immune-checkpoint targeting. DESIGN: Two immunotherapy-resistant HCC models were generated by serial orthotopic implantation of HCC cells through anti-PD-L1-treated syngeneic, immunocompetent mice and interrogated by single-cell RNA sequencing (scRNA-seq), genomic and immune profiling. Key signalling pathway was investigated by lentiviral-mediated knockdown and pharmacological inhibition, and further verified by scRNA-seq analysis of HCC tumour biopsies from a phase II trial of pembrolizumab (NCT03419481). RESULTS: Anti-PD-L1-resistant tumours grew >10-fold larger than parental tumours in immunocompetent but not immunocompromised mice without overt genetic changes, which were accompanied by intratumoral accumulation of myeloid-derived suppressor cells (MDSC), cytotoxic to exhausted CD8(+) T cell conversion and exclusion. Mechanistically, tumour cell-intrinsic upregulation of peroxisome proliferator-activated receptor-gamma (PPARγ) transcriptionally activated vascular endothelial growth factor-A (VEGF-A) production to drive MDSC expansion and CD8(+) T cell dysfunction. A selective PPARγ antagonist triggered an immune suppressive-to-stimulatory TME conversion and resensitised tumours to anti-PD-L1 therapy in orthotopic and spontaneous HCC models. Importantly, 40% (6/15) of patients with HCC resistant to pembrolizumab exhibited tumorous PPARγ induction. Moreover, higher baseline PPARγ expression was associated with poorer survival of anti-PD-(L)1-treated patients in multiple cancer types. CONCLUSION: We uncover an adaptive transcriptional programme by which tumour cells evade immune-checkpoint targeting via PPARγ/VEGF-A-mediated TME immunosuppression, thus providing a strategy for counteracting immunotherapeutic resistance in HCC. BMJ Publishing Group 2023-09 2023-04-05 /pmc/articles/PMC10423534/ /pubmed/37019619 http://dx.doi.org/10.1136/gutjnl-2022-328364 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Hepatology
Xiong, Zhewen
Chan, Stephen Lam
Zhou, Jingying
Vong, Joaquim S.L.
Kwong, Tsz Tung
Zeng, Xuezhen
Wu, Haoran
Cao, Jianquan
Tu, Yalin
Feng, Yu
Yang, Weiqin
Wong, Patrick Pak-Chun
Si-Tou, Willis Wai-Yiu
Liu, Xiaoyu
Wang, Jing
Tang, Wenshu
Liang, Zhixian
Lu, Jiahuan
Li, Ka Man
Low, Jie-Ting
Chan, Michael Wing-Yan
Leung, Howard H.W.
Chan, Anthony W.H.
To, Ka-Fai
Yip, Kevin Yuk-Lap
Lo, Yuk Ming Dennis
Sung, Joseph Jao-Yiu
Cheng, Alfred Sze-Lok
Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
title Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
title_full Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
title_fullStr Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
title_full_unstemmed Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
title_short Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
title_sort targeting ppar-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma
topic Hepatology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10423534/
https://www.ncbi.nlm.nih.gov/pubmed/37019619
http://dx.doi.org/10.1136/gutjnl-2022-328364
work_keys_str_mv AT xiongzhewen targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT chanstephenlam targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT zhoujingying targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT vongjoaquimsl targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT kwongtsztung targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT zengxuezhen targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT wuhaoran targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT caojianquan targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT tuyalin targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT fengyu targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT yangweiqin targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT wongpatrickpakchun targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT sitouwilliswaiyiu targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT liuxiaoyu targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT wangjing targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT tangwenshu targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT liangzhixian targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT lujiahuan targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT likaman targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT lowjieting targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT chanmichaelwingyan targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT leunghowardhw targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT chananthonywh targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT tokafai targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT yipkevinyuklap targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT loyukmingdennis targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT sungjosephjaoyiu targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma
AT chengalfredszelok targetingppargammacounteractstumouradaptationtoimmunecheckpointblockadeinhepatocellularcarcinoma