IDDF2020-ABS-0201 Targeting hepatoma-intrinsic pparγ signaling overcomes immune checkpoint therapy resistance by inflaming the tumor microenvironment

BackgroundImmune-checkpoint blockade (ICB) therapies by antibodies against programmed death 1 (PD1)/PD1 ligand 1 (PD-L1) axis have revolutionized the treatment paradigm for cancer. Although subsets of people exhibit durable responses, ICB resistance has increasingly been observed, especially in hepatocellular carcinoma (HCC). Here we utilized a single-cell RNA-sequencing (scRNA-seq) approach to elucidate the tumor-intrinsic mechanism underlying tumor immunosuppression and ICB resistance.MethodsWe first recapitulated the clinical outcome of ICB resistance via repeated cycles of in vivo selection in orthotopic murine models of HCC. To investigate the tumor cell-extrinsic resistant factors, the myeloid and lymphoid immune populations were profiled by multi-color flow cytometry. To dissect hepatoma-intrinsic resistant signatures, we performed scRNA-seq from anti-PD-L1-treated tumors generated from parental or PD-L1R Hepa1-6 cells. The anti-tumor efficacy and immunophenotype of combined therapy with anti-PD-L1 antibody and peroxisome proliferator-activated receptor gamma (PPARγ) antagonist T0070907 were further determined. To demonstrate the clinical relevance of PPARγ, we performed scRNA-seq analysis of tumor biopsies from advanced HCC patients who received anti-PD-1 treatment.ResultsWe successfully established anti-PD-L1-resistance models, which were accompanied with lower CD8+T cells and T helper 1 (TH1) cells but higher exhausted T cells and myeloid-derived suppressor cells (MDSCs). Integrative gene expression analysis showed significant enrichment of PPARγ signaling in PD-L1R tumor cells. Importantly, T0070907 overcame ICB resistance in HCC, which was accompanied with enhanced cytolytic activity and reduced T cell exhaustion and decreased infiltration of MDSCs. Notably, scRNA-seq profiles of human biopsies uncovered adaptive upregulation of tumor-cell intrinsic PPARγ and re-shaping of T cell exhaustion in non-responders upon anti-PD-1 therapy.ConclusionsTaken together, hepatoma-intrinsic PPARγ activation might be associated with immune evasion and ICB resistance. Pharmacological inhibition of PPARγ sensitized tumors to anti-PD-L1 therapy, thus representing a promising strategy to overcome ICB resistance.