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

Abstract

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.

Identification of PPAR‐related differentially expressed genes liver hepatocellular carcinoma and construction of a prognostic model based on data analysis and molecular docking

“…PPARγ is the most extensively studied subtype, and its aberrantly high expression in HCC is associated with metabolic dysregulation and tumour progression 32 . Moreover, since PPARγ overexpression plays a potential role in tumour immune escape, simultaneous inhibition of PPARγ and immune checkpoints can reshape the immune landscape of liver tumours, and overcome resistance to immune checkpoint blockers 33 …”

“… 32 Moreover, since PPARγ overexpression plays a potential role in tumour immune escape, simultaneous inhibition of PPARγ and immune checkpoints can reshape the immune landscape of liver tumours, and overcome resistance to immune checkpoint blockers. 33 …”

Quantitative proteomics assay reveals G protein-coupled receptor kinase 4-induced HepG2 cell growth inhibition

“…This investigation did not observe any changes in PPAR expression that were induced by GRK4. It was revealed that GRK4 and PPARs are significant regulators of hypertension and HCC [ 6 , 15 , [29] , [30] , [31] , [32] ]. Although there has been no evidence that GRK4 impacts the PPAR, it was discovered that GRK2, a member of the GRK family, might be the cause of hypertension due to overexpression and PPAR downregulation [ 33 ].…”

Clinico‐histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease

“…On the other hand, a recent international retrospective real‐world study comparing atezolizumab plus bevacizumab vs. anti‐VEGF lenvatinib or sorafenib as the first‐line treatment for unresectable HCC confirmed that treatment with lenvatinib was significantly associated with longer overall survival (hazard ratio [HR], 0.46) and progression‐free survival (HR, 0.55) in the NAFL/NASH subgroup, although there was no difference in patients with non‐NAFL/NASH 25 . Given that NAFLD‐HCC may be characterized by distinct molecular features as described below, metabolism‐mediating drugs such as metformin and a selective peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) antagonist may restore anti‐PD‐1 treatment efficacy in NASH by rescuing dysfunctional CD8 T cells 35,36 …”