Personalized identification of tumor-associated immunogenic neoepitopes in hepatocellular carcinoma in complete remission after sorafenib treatment
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Sindy Vrecko1, David Guenat1,2,3,4, Patricia Mercier-Letondal1, Hugues Faucheu1,3, Magalie Dosset1,2, Bernard Royer1,5, Jeanne Galaine1, Romain Boidot6, Stefano Kim7, Marine Jary1,7, Olivier Adotévi1,7, Christophe Borg1,7 and Yann Godet1
1University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon F-25000, France
2University Bourgogne Franche-Comté, LabEx LipSTIC ANR-11-LABX-0021, Besançon F-25000, France
3University Hospital of Besançon, Department of Molecular and Cell Biology, Besançon F-25000, France
4Stanford Cancer Institute, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA
5University Hospital of Besançon, Department of Pharmacology, Besançon F-25000, France
6Centre Georges-François Leclerc, Platform of Transfer in Cancer Biology, Department of Biology and Pathology of Tumours, Centre de Recherche INSERM LNC-UMR123, Dijon F-21000, France
7University Hospital of Besançon, Department of Medical Oncology, Besançon F-25000, France
Yann Godet, email: [email protected]
Keywords: neoepitopes; mutations; hepatocellular carcinoma; CD4 T cells; sorafenib
Abbreviations: HCC: Hepatocellular Carcinoma; MoDC: Monocyte derived Dendritic Cells; PBMC: Peripheral Mononuclear Cells; SNVs: Single-Nucleotide Variants; WES: Whole Exome Sequencing
Received: June 23, 2018 Accepted: October 08, 2018 Published: October 23, 2018
Sorafenib, a multi-targeted kinase inhibitor, is the current standard systemic treatment for advanced hepatocellular carcinoma. Sorafenib has anti-angiogenic and anti-proliferative properties and is also known to favor anti-tumor T cell responses by reducing the population of immunosuppressive cells such as Treg and MDSC. Anti-tumor immune responses, especially mediated by CD4+ T-cells, are critical for tumor cells eradication and therapies modulating those responses are appealing in a growing number of cancers.
Here, we report and investigate the case of a patient diagnosed with an advanced HCC treated by sorafenib who experienced a complete histological response. We aimed to identify immunogenic peptides derived from tumor mutated proteins that stimulated CD4+ T cells responses thus favoring the exceptional recovery process of this patient.
Tumor neoantigens were identified using whole exome sequencing of normal and tumor tissue and peptide MHC binding prediction algorithms. Among 442 tumor-specific somatic variants, 50 missense mutations and 20 neoepitopes predicted to bind MHC-II were identified. Candidate neoepitopes immunogenicity was assessed by IFN-γ ELISpot after culture of patient’s PBMCs in presence of synthetic neopeptides.
CD4+ memory T cell responses were detected against a mutated IL-1βS230F peptide and two additional neoepitopes from HELZ2V241M and MLL2A4458V suggesting that efficient anti-tumor immune response occurred in this patient. These results showed that T cells can recognize neoantigens and may lead to the cancer elimination after immunomodulation in the tumor-microenvironment induced by sorafenib. This observation indicates that other immunotherapies in combination with sorafenib could potentially increase the response rate in HCC at advanced stage.
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