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

Autor: Zhewen Xiong, Stephen Lam Chan, Jingying Zhou, Joaquim S.L. Vong, Tsz Tung Kwong, Xuezhen Zeng, Haoran Wu, Jianquan Cao, Yalin Tu, Yu Feng, Weiqin Yang, Patrick Pak-Chun Wong, Willis Wai-Yiu Si-Tou, Xiaoyu Liu, Jing Wang, Wenshu Tang, Zhixian Liang, Jiahuan Lu, Ka Man Li, Jie-Ting Low, Michael Wing-Yan Chan, Howard H.W. Leung, Anthony W.H. Chan, Ka-Fai To, Kevin Yuk-Lap Yip, Yuk Ming Dennis Lo, Joseph Jao-Yiu Sung, Alfred Sze-Lok Cheng
Rok vydání: 2023
Předmět:
Zdroj: Gut. :gutjnl-2022
ISSN: 1468-3288
0017-5749
DOI: 10.1136/gutjnl-2022-328364
Popis: ObjectiveTherapy-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.DesignTwo 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).ResultsAnti-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.ConclusionWe 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.
Databáze: OpenAIRE
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