Project description:The DNAJB1-PRKACA fusion transcript is the oncogenic driver in fibrolamellar hepatocellular carcinoma, a lethal disease lacking specific therapies. This study reports on the identification, characterization, and immunotherapeutic application of HLA-presented neoantigens specific for the DNAJB1-PRKACA fusion transcript in fibrolamellar hepatocellular carcinoma. DNAJB1-PRKACA-derived HLA class I and HLA class II ligands induce multifunctional cytotoxic CD8+ and T-helper 1 CD4+ T cells, and their cellular processing and presentation in DNAJB1-PRKACA expressing tumor cells is demonstrated by mass spectrometry-based immunopeptidome analysis. Single-cell RNA sequencing further identifies multiple T cell receptors from DNAJB1-PRKACA-specific T cells. Vaccination of a fibrolamellar hepatocellular carcinoma patient, suffering from recurrent short interval disease relapses, with DNAJB1-PRKACA-derived peptides under continued Poly (ADP-ribose) polymerase inhibitor therapy induces multifunctional CD4+ T cells, with an activated T-helper 1 phenotype and high T cell receptor clonality. Vaccine-induced DNAJB1-PRKACA-specific T cell responses persist over time and, in contrast to various previous treatments, are accompanied by durable relapse free survival of the patient for more than 21 months post vaccination. Our preclinical and clinical findings identify the DNAJB1-PRKACA protein as source for immunogenic neoepitopes and corresponding T cell receptors and provide efficacy in a single-patient study of T cell-based immunotherapy specifically targeting this oncogenic fusion.
Project description:A Cartes d'Identite des Tumeurs (CIT) project from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net) | Affymetrix HG-U133 Plus 2.0 : 5 mixed fibrolamellar carcinoma (m-FLC), 17 pure fibrolamellar carcinoma (p-FLC), 7 hepatocelluar carcinoma arising in non-cirrhotic liver (nc-HCC) and 10 non-tumoral livers (NL).
Project description:Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. A cohort of FLCs was analyzed through SNP-array. GISTIC algorithm identified chromosomal aberrations.
Project description:Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer usually developed in non-cirrhotic livers of children and young adults with unknown etiology. Treatment is limited to surgical intervention. To date, molecular pathogenesis of FLC has been poorly characterized. A cohort of FLCs was analyzed through SNP-array. GISTIC algorithm identified chromosomal aberrations. FLC tumors corresponding to 25 different patients. In all cases, tumor and corresponding non-tumor samples were frozen (-80°C) after hepatic resection at diagnosis. Comparative Genomic Hybridization analysis was done using Illumina HumanHap370CNV Genotyping BeadChip SNP array
Project description:Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare variant of HCC that most frequently affects young adults. Because of its rarity and an absence of preclinical models, the molecular biology of FL-HCC remains unclear. Our objective was to analyze chromosomal alterations and dysregulated gene expression in tumor specimens collected at a single center during two decades of experience with FL-HCC.
Project description:Fibrolamellar hepatocellular carcinoma(FLC) is a rare form of cancer that affects primarily adolescentsand young adults. FLC tumors are typically associated with an intrachromosomal deletion resulting in expression of a fusion protein between the chaperone DNAJ1B and the protein kinase PKA. FLC ischallenging to study because of its rarity and limited pre-clinical models. Here, we developed a novel transgenic mouse model of FLC. In this model, DNAJ1B-PKA expression in the liver of mouse embryos results in perinatal lethalityassociated with liver developmental defects, while DNAJ1B-PKA expression in the liver of adult mice initiates tumors resembling FLC at low penetrance. Some of these tumors can be serially propagated in 3D cultures and in allografts, including in syngeneic hosts. One such model shows growth inhibition upon treatment with the CDK4/6 inhibitor palbociclib. New pre-clinical models of FLC will provide novel insights into the biology of this rare cancerand may help identify novel therapeutic strategies.
Project description:The etiology of fibrolamellar hepatocellular carcinoma (FL-HCC), a liver cancer occurring increasingly in children to young adults, is poorly understood. We performed high-throughput sequencing on mRNA isolated from a newly developed model of FL-HCC and 4 different maturational lineages of the hepatobiliary system. Our results indicate that the transcriptome of FL-HCC is most similar to that of biliary tree stem cells.