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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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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 |
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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 |
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