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

作者：Zhewen Xiong, Stephen Lam Chan, Jingying Zhou, Joaquim S. L. Vong, Tsz Tung Kwong, Xuezhen Zeng, Haoran Wu, Jian 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 W.Y. Chan, Howard H.W. Leung, Anthony W.H. Chan, Ka‐Fai To, Kevin Yuk-Lap Yip, Yuk Ming Dennis Lo, Joseph J.�Y. Sung, Alfred Sze‐Lok Cheng · 发表于：Gut · 年份：2023 · DOI：10.1136/gutjnl-2022-328364 · 被引用次数：115 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Immune cells in cancer

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-stimul...