Müller, Tobias

4100 Background: Checkpoint inhibition with anti-PD1 is able to elicit objective response rates (ORR) of ̃ 20% in patients with advanced hepatocellular carcinoma (aHCC) but molecular biomarkers predicting response remain unknown. Here, we define biomarkers of response and primary resistance to anti-PD1 in aHCC by analyzing molecular features prior to systemic therapy. Methods: Through an international consortium of 13 referral centers, we gathered 111 fresh and archived tumor samples from patients with advanced HCC treated with single agent anti- PD1 therapy. Genomic analysis was performed with whole genome expression arrays, CTNNB1 exon 3 mutation assessment and histological evaluation. Results: Overall, we performed transcriptomic analysis in 83 patients, 28 of which were treated in first-line (ORR: 42.9%) while the remaining 55 patients were treated either in 2nd (41 patients, ORR 29.3%) or 3rd line (14 patients, ORR 7.1%) after prior therapy with tyrosine- kinase inhibitors (TKI) sorafenib or lenvatinib. In patients treated in frontline, response was associated with a significant upregulation in Interferon-γ signaling (IFNγ) and genesets relatedto the antigen presentation machinery (FDR < 0.05). Through differential expression analysis we defined an 11-gene signature that was significantly associated with both major pathways (FDR < 0.01) and was capable of predicting OR as well as progression-free- (PFS) and overall survival (OS) in patients with aHCC. The signature was validated in three independent cohorts of melanoma, lung cancer, and head and neck squamous cell cancer patients were high expression was associated with a significant increase in ORR and longer PFS. In HCC, high expression of the signature was associated with a distinct profile in the immune infiltrate, where an increase in M1 macrophages (p = 0.003), CD4 memory T cell (p < 0.01) and CD4 naïve T cell-infiltration (p = 0.026) was observed. Conversely, low expression of the signature was associated with a marked upregulation of regulatory T cells (p < 0.001). No association was found, however, between either the overall immune infiltrate or CTNNB1 mutations and response. In patients that were treated with TKIs in frontline before receiving subsequent anti-PD1 therapy, the signature was no longer able to predict either OR or PFS/OS, suggesting that TKIs may reshape the microenvironment in a way that renders previously inflamed tumors no longer amenable to anti-PD1. Conclusions: Here, we define an 11-gene signature of response to anti-PD1 in first line aHCC. The signature was validated in patients with other solid cancer types, where it retained its predictive ability. Of note, the signature was not able to identify responders among HCC patients that were treated with TKIs prior to anti-PD1 therapy. The molecular changes induced by different treatment lines would, thus, require fresh biopsies prior to anti-PD1to enable biomarker-driven treatment.

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.