Personalized identification of tumor-associated immunogenic neoepitopes in hepatocellular carcinoma in complete remission after sorafenib treatment.
Fiche publication
Date publication
octobre 2018
Journal
Oncotarget
Auteurs
Membres identifiés du Cancéropôle Est :
Pr ADOTEVI Olivier, Dr BOIDOT Romain, Pr BORG Christophe, Dr GODET Yann, Dr ROYER Bernard, Dr KIM Stephano, Dr GALAINE Jeanne
Tous les auteurs :
Vrecko S, Guenat D, Mercier-Letondal P, Faucheu H, Dosset M, Royer B, Galaine J, Boidot R, Kim S, Jary M, Adotévi O, Borg C, Godet Y
Lien Pubmed
Résumé
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-1β peptide and two additional neoepitopes from HELZ2 and MLL2 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.
Mots clés
CD4 T cells, hepatocellular carcinoma, mutations, neoepitopes, sorafenib
Référence
Oncotarget. 2018 Oct 23;9(83):35394-35407